Improving the Stability, Dissolution, and Bioavailability of Isotretinoin by Cocrystallization

Abstract

Isotretinoin (13-cis retinoic acid, ITT) is a gold standard therapy for the treatment of severe acne. However, because of its poor absorption, ITT must be taken with fatty meals to increase bioavailability. The coadministration of food could reduce the compliance of patients and increase the risk of inconsistent serum levels because of different eating habits. In this work, we designed and synthesized four cocrystals of ITT. The cocrystal between ITT and ethyl nicotinate (ENT), namely, ITT-ENT, presented better chemical stability, dissolution, and absorption than ITT itself. The AUC 0−10h of ITT-ENT cocrystal capsules is 2.6 times as that of the commercially available ITT capsules in the fasted state. Because of the high bioavailability in the fasted state, the food has a marginal effect on the absorption of cocrystal capsules. This work sets a good example for applying cocrystal technology to enhance the absorption and mitigate the food effect of drugs.

Pyrazinamide-3-Nitrophthalic Acid Cocrystals: Synthesis, Transformation, and Property Evaluation

“…Compared to the PZA monomer, 3-NPA in PZA-3-NPA cocrystals enhanced the dissolution ability of PZA, rendering PZA-3-NPA cocrystals with diverse ratios follow the similar “spring-hover” behavior in the study. However, the enhanced dissolution behavior of the cocrystals was not very obvious when compared with PZA, but the dissolution behavior of the cocrystals was still reported here based on the following consideration: First, compared to PZA, the dissolution behavior of the cocrystals was not significantly improved, but when compared with the coformer (3-NPA), the dissolution behavior of the cocrystals was strongly affected, which was contrary to the previous reports (the better the coformer property, the better the cocrystal property). , …”

“…However, the enhanced dissolution behavior of the cocrystals was not very obvious when compared with PZA, but the dissolution behavior of the cocrystals was still reported here based on the following consideration: First, compared to PZA, the dissolution behavior of the cocrystals was not significantly improved, but when compared with the coformer (3-NPA), the dissolution behavior of the cocrystals was strongly affected, which was contrary to the previous reports (the better the coformer property, the better the cocrystal property). 35,36 Second, the dissolution behavior of the cocrystals reported here was used to investigate the effect of stoichiometric ratio change in pyrazinamide-3-nitrophthalic acid cocrystals (1:1, 1:2, and 2:1); it can be seen that the change in the stoichiometric ratios of pyrazinamide-3-nitrophthalic acid cocrystals displayed different dissolution behavior, given the following sequence of dissolution rate: 1:2 cocrystal > 2:1 cocrystal > 1:1 cocrystal > PZA, which was inconsistent with the Hirshfeld analysis but may be ascribed to the diverse chemical structure of these cocrystals. PXRD (Figure S3) results revealed that 1:1 PZA-3-NPA cocrystal and 1:2 PZA-3-NPA cocrystal were partially converted into pure PZA, while 2:1 PZA-3-NPA cocrystals were all transformed into pure PZA in the simulated gastric juice environment (pH = 1.2).…”

New Cocrystals of Ligustrazine: Enhancing Hygroscopicity and Stability

“…The pharmaceutical cocrystal is defined as a single-phase crystalline solid composed of an active pharmaceutical ingredient (API) and coformers (CCFs) combined in the same crystal lattice through noncovalent interactions in a certain stoichiometric ratio [1][2][3][4]. The formation of cocrystals could improve the poor physicochemical properties of API without modifying the chemical structure [5][6][7][8][9][10][11][12][13][14][15][16].…”

Crystal Engineering to Solidify and Chemically Stabilize Oily dl-Butylphthalide

“…15 This approach provides valuable opportunities to modulate the physicochemical properties of compounds that lack ionizable functional groups. We have previously enhanced the stability of Vitamin D 3 , 16 nicorandil, 17 and L-menthol, 18 and the bioavailability of baicalein, 19 abiraterone acetate, 20 and isotretinoin 21 through solid-state modification. Furthermore, some liquid/oily substances have been successfully converted to solids by cocrystallization.…”