The purpose of the present study was to investigate the effect of the coformer difference on particle surface solution-mediated phase transformation (PS-SMPT) during cocrystal particle dissolution in aqueous media in the absence and presence of polymers. SMPT can occur either in the bulk phase or at the particle surface because drug molecules can be supersaturated at the dissolving cocrystal surface, as well as in the bulk phase. Previously, bulk phase SMPT has been primarily investigated in formulation development. However, little is known about the effects of coformers and polymers on PS-SMPT of cocrystals. In this study, six carbamazepine (CBZ) cocrystals were used as model cocrystals (malonic acid (MAL), succinic acid (SUC), glutaric acid (GLA), adipic acid (ADP), saccharin (SAC), and nicotinamide (NCT); nonsink dissolution tests were performed with or without a precipitation inhibitor (hydroxypropyl methylcellulose (HPMC)) at pH 6.5. The residual particles were analyzed by powder X-ray diffraction, differential scanning calorimetry, polarized light microscopy (PLM), and scanning electron microscopy. Real-time PLM was used to directly observe rapid PS-SMPT. In the absence of HPMC, supersaturation was not observed in the bulk phase for all cocrystals. All cocrystals rapidly transformed to CBZ dihydrate aggregates via PS-SMPT (mostly within 1 min). In contrast, in the presence of 0.1% HPMC, supersaturation was observed for CBZ-SUC, CBZ-ADP, CBZ-SAC, and CBZ-NCT but not for CBZ-MAL and CBZ-GLA. The cocrystals with lower solubility coformers tended to induce higher supersaturation in the bulk phase. The PS-SMPT of CBZ-SUC, CBZ-ADP, and CBZ-SAC was slowed down by HPMC. By suppressing PS-SMPT, the cocrystals exhibited its supersaturation potential, depending on the properties of each coformer. To take advantage of the supersaturation potential of cocrystals to improve oral drug absorption, it is important to suppress particle surface SMPT in addition to bulk phase SMPT.

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Supersaturable active pharmaceutical ingredients (sAPI), such as salts, cocrystals, and amorphous solids, can form supersaturated solutions after dissolving in the gastrointestinal fluids. However, there are cases in which supersaturation is not observed in an in vitro nonsink dissolution test. The purpose of the present study was to investigate the mechanisms of supersaturation suppression in the dissolution process of acidic drug salts. Diclofenac sodium (DCF Na, pK a = 4.0) was employed as a model drug. DCF Na APIs and tablets (25 mg, 0.08 mmol) showed little or no supersaturation at pH 1.2 (compendial paddle apparatus, 500 mL, 50 rpm). However, marked supersaturation was observed at pH 2.0 and 3.0. The liquid–liquid phase separation (LLPS) of DCF free acid (FA) was observed in the surrounding of the DCF Na particles immediately after contact with acidic media. Particularly at pH 1.2, the surface of DCF Na was immediately covered with the liquid (oil) layer of DCF FA. The DCF FA liquid layer started to crystallize within several minutes. The LLPS concentration of DCF FA (0.30 mM) was twice as high as the theoretical maximum concentration after the complete dissolution of DCF Na in the dissolution test (0.16 mM). In addition, in the bulk phase precipitation test at 0.16 mM, rapid concentration reduction was not observed within 1 h in the bulk media. Taken together, these results suggest that the LLPS (and subsequent crystallization) of DCF FA on the surface of DCF Na particles rather than in the bulk medium is more likely to have suppressed the supersaturation from DCF Na.

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