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. 2018 Jan;107(1):380-389.
doi: 10.1016/j.xphs.2017.09.014. Epub 2017 Oct 6.

Mechanistic Basis of Cocrystal Dissolution Advantage

Fengjuan Cao  1 , Gordon L Amidon  1 , Naír Rodríguez-Hornedo  1 , Gregory E Amidon  2
Affiliations

Mechanistic Basis of Cocrystal Dissolution Advantage

Fengjuan Cao et al. J Pharm Sci. 2018 Jan.

Abstract

Current interest in cocrystal development resides in the advantages that the cocrystal may have in solubility and dissolution compared with the parent drug. This work provides a mechanistic analysis and comparison of the dissolution behavior of carbamazepine (CBZ) and its 2 cocrystals, carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) under the influence of pH and micellar solubilization. A simple mathematical equation is derived based on the mass transport analyses to describe the dissolution advantage of cocrystals. The dissolution advantage is the ratio of the cocrystal flux to drug flux and is defined as the solubility advantage (cocrystal to drug solubility ratio) times the diffusivity advantage (cocrystal to drug diffusivity ratio). In this work, the effective diffusivity of CBZ in the presence of surfactant was determined to be different and less than those of the cocrystals. The higher effective diffusivity of drug from the dissolved cocrystals, the diffusivity advantage, can impart a dissolution advantage to cocrystals with lower solubility than the parent drug while still maintaining thermodynamic stability. Dissolution conditions where cocrystals can display both thermodynamic stability and a dissolution advantage can be obtained from the mass transport models, and this information is useful for both cocrystal selection and formulation development.

Keywords: absorption; co-crystals; diffusion; dissolution; dissolution rate; mathematical model; solubility.

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Figures

Figure 1
Figure 1
a) Eutectic concentrations of CBZ ( formula image) and SAC ( formula image) measured at the eutectic point for CBZ-SAC at pH 1 as a function of SLS concentration. b) Keu values calculated from the eutectic concentrations.
Figure 2
Figure 2
a) Eutectic concentrations of CBZ ( formula image) and SLC ( formula image) measured at the eutectic point for CBZ-SLC at pH 1 as a function of SLS concentration. b) Keu values calculated from the eutectic concentrations.
Figure 3
Figure 3
a) Solubility of CBZD ( formula image) and CBZ-SAC ( formula image) at pH 1 as a function of SLS concentration. b) Solubility advantage of CBZ-SAC, Scc/Sdrug, calculated from the solubility data.
Figure 4
Figure 4
a) Solubility of CBZD ( formula image) and CBZ-SLC ( formula image) at pH 1 as a function of SLS concentration. b) Solubility advantage of CBZ-SLC, Scc/Sdrug, calculated from the solubility data.
Figure 5
Figure 5
a) Flux of CBZD ( formula image) and CBZ-SAC ( formula image) at pH 1 as a function of SLS concentration. b) Dissolution advantage (∅) of CBZ-SAC calculated from the experimental flux.
Figure 6
Figure 6
a) Flux of CBZD ( formula image) and CBZ-SLC ( formula image) at pH 1 as a function of SLS concentration. b) Dissolution advantage (∅) of CBZ-SLC calculated from the experimental flux.
Figure 7
Figure 7
Micellar diffusivities of CBZ determined from the dissolution of CBZD ( formula image), CBZSAC ( formula image) and CBZ-SLC ( formula image) at pH 1 as a function of SLS. The circles represent the experimental data and the solid lines represent the power regression analyses.
Figure 8
Figure 8
Solubility ( formula image) and dissolution ( formula image) enhancements of CBZD (a), CBZ-SAC (b) and CBZ-SLC (c) at pH 1 as a function of SLS. Both solubility and dissolution enhancements were determined by normalizing the data to 22 mM SLS.
Figure 9
Figure 9
Solubility ( formula image) and dissolution ( formula image) advantage of CBZ-SAC (a) and CBZ-SLC (b) at pH 1 as a function of SLS.
Figure 10
Figure 10
a) Flux of CBZD and CBZ-SAC at 400 mM SLS as a function of bulk pH. b) Dissolution advantage, ∅, of CBZ-SAC calculated from the experimental flux. The flux of CBZD ( formula image) is predicted using equation 4 and the flux of CBZ-SAC ( formula image) is predicted using equation 5. CBZD experimental flux: formula image; CBZ-SAC experimental flux: formula image.
Figure 11
Figure 11
a) Flux of CBZD and CBZ-SLC at 44 mM SLS as a function of bulk pH. b) Dissolution advantage, ∅, of CBZ-SLC calculated from the experimental flux. The flux of CBZD ( formula image) is predicted using equation 4 and the flux of CBZ-SLC ( formula image) is predicted using equation 5. CBZD experimental flux: formula image; CBZ-SAC experimental flux: formula image.
Figure 12
Figure 12
(a) Theoretical flux comparison of CBZD (yellow) to CBZ-SAC (blue), and (b) CBZD (yellow) to CBZ-SLC (purple) as a function of pH and SLS concentration. Flux predictions of CBZD were determined using equation 4 and cocrystals were from reference.
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