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Cocrystal formulations: Evaluation of the impact of excipients on dissolution by molecular simulation and experimental approaches

Cocrystal formulations: Evaluation of the impact of excipients on dissolution by molecular simulation and experimental approaches
Cocrystal formulations: Evaluation of the impact of excipients on dissolution by molecular simulation and experimental approaches
Cocrystallization has matured into an established technique for fine-tuning the physicochemical properties of active pharmaceutical ingredients (APIs). This technique has been adopted by pharmaceutical drug companies, with increasing numbers of cocrystal-based drug products now entering the market. Surprisingly, however, studies into the formulation aspects of cocrystal-based drugs are relatively few and far between compared to the vast literature on their design, synthesis, and characterization. We herein report the results of our investigations into cocrystal–excipient interactions in water that determine the dissolution properties of cocrystals in formulation by a combination of molecular dynamics (MD) simulation and experimental approaches. Two cocrystals of an antirheumatic drug, leflunomide (LEF) with 3-hydroxybenzoic acid (HBA) and 2-picolinic acid (PIC), were assessed in formulation with the frequently used excipients lactose and dibasic calcium phosphate (DCP). For comparison, the dissolution of neat LEF formulations with these excipients was also evaluated. The parameters deduced from MD simulations, such as solvent-accessible surface area, intermolecular hydrogen bonds among formulation ingredients and water, and interaction energy between the API (or cocrystal) and water were found to be essential indicators in the prediction of cocrystal formulation dissolution trends. It was found that the presence of lactose as an excipient improved the dissolution of the cocrystal formulation compared to the neat cocrystals, most notably for the LEF-PIC cocrystal. In contrast, DCP was seen to have a detrimental effect on the dissolution of cocrystal formulations, all exhibiting lower dissolution than their neat cocrystal counterparts and LEF. Careful analysis of these results revealed that the nature of the excipient plays a significant role in the dissolution properties. While the improved dissolution of the lactose formulations was attributed to its hydrophilic nature, the ionic and hydrophobic nature of DCP was likely responsible for its detrimental effect. The results of the MD simulations were found to be in excellent agreement with the experimentally observed dissolution hierarchy.
1528-7483
1006-1018
Cadden, Joseph
86c93935-5d3e-4c0c-bd73-af51f60c9d1c
Gupta, Krishna M.
49d95187-1896-423f-9474-c51039be301f
Kanaujia, Parijat
3e146762-e91e-4d9c-9e30-28f311798626
Coles, Simon J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Aitipamula, Srinivasulu
e1ca2522-d14f-4f82-89ab-1996a021582a
Cadden, Joseph
86c93935-5d3e-4c0c-bd73-af51f60c9d1c
Gupta, Krishna M.
49d95187-1896-423f-9474-c51039be301f
Kanaujia, Parijat
3e146762-e91e-4d9c-9e30-28f311798626
Coles, Simon J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Aitipamula, Srinivasulu
e1ca2522-d14f-4f82-89ab-1996a021582a

Cadden, Joseph, Gupta, Krishna M., Kanaujia, Parijat, Coles, Simon J. and Aitipamula, Srinivasulu (2021) Cocrystal formulations: Evaluation of the impact of excipients on dissolution by molecular simulation and experimental approaches. Crystal Growth & Design, 21 (2), 1006-1018. (doi:10.1021/acs.cgd.0c01351).

Record type: Article

Abstract

Cocrystallization has matured into an established technique for fine-tuning the physicochemical properties of active pharmaceutical ingredients (APIs). This technique has been adopted by pharmaceutical drug companies, with increasing numbers of cocrystal-based drug products now entering the market. Surprisingly, however, studies into the formulation aspects of cocrystal-based drugs are relatively few and far between compared to the vast literature on their design, synthesis, and characterization. We herein report the results of our investigations into cocrystal–excipient interactions in water that determine the dissolution properties of cocrystals in formulation by a combination of molecular dynamics (MD) simulation and experimental approaches. Two cocrystals of an antirheumatic drug, leflunomide (LEF) with 3-hydroxybenzoic acid (HBA) and 2-picolinic acid (PIC), were assessed in formulation with the frequently used excipients lactose and dibasic calcium phosphate (DCP). For comparison, the dissolution of neat LEF formulations with these excipients was also evaluated. The parameters deduced from MD simulations, such as solvent-accessible surface area, intermolecular hydrogen bonds among formulation ingredients and water, and interaction energy between the API (or cocrystal) and water were found to be essential indicators in the prediction of cocrystal formulation dissolution trends. It was found that the presence of lactose as an excipient improved the dissolution of the cocrystal formulation compared to the neat cocrystals, most notably for the LEF-PIC cocrystal. In contrast, DCP was seen to have a detrimental effect on the dissolution of cocrystal formulations, all exhibiting lower dissolution than their neat cocrystal counterparts and LEF. Careful analysis of these results revealed that the nature of the excipient plays a significant role in the dissolution properties. While the improved dissolution of the lactose formulations was attributed to its hydrophilic nature, the ionic and hydrophobic nature of DCP was likely responsible for its detrimental effect. The results of the MD simulations were found to be in excellent agreement with the experimentally observed dissolution hierarchy.

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Manuscript_CGD_30112020 JC SC (003) - Accepted Manuscript
Restricted to Repository staff only until 22 December 2021.
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More information

Accepted/In Press date: 10 December 2020
e-pub ahead of print date: 22 December 2020
Published date: 3 February 2021

Identifiers

Local EPrints ID: 446274
URI: http://eprints.soton.ac.uk/id/eprint/446274
ISSN: 1528-7483
PURE UUID: 62eb8666-f542-44fc-a24d-6d6fd900fede
ORCID for Simon J. Coles: ORCID iD orcid.org/0000-0001-8414-9272

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Date deposited: 03 Feb 2021 17:34
Last modified: 05 Mar 2021 02:35

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Contributors

Author: Joseph Cadden
Author: Krishna M. Gupta
Author: Parijat Kanaujia
Author: Simon J. Coles ORCID iD
Author: Srinivasulu Aitipamula

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