Influence of Excipients on Cocrystal Stability and Formation

Cocrystal formation is widely used to modify and optimize the physicochemical properties of an active pharmaceutical ingredient (API). However, the stability of cocrystals toward formulation with excipients is little investigated. In this work, the effect of grinding in the presence of the common excipients polyvinylpyrrolidone (PVP) and microcrystalline cellulose (MCC) on 11 cocrystals and a salt of the sulfonamide diuretic chlorothiazide (ctz) was studied (ctz-bipy, ctz-ebipy, ctz-pbipy, ctz-pyr, ctzhyp, ctz-hma, ctz-bza, ctz-nia, ctz-ina, ctz-cbz, ctz-aca, ctz-ppa, (bzamH(+))(ctz(-)); bipy = 4,4'-bipyridine, ebipy = 1,2-di(4-pyridyl)ethylene, pbipy = 1,3-di(4-pyridyl)propane, pyr = pyrazine, hyp = 2-hydroxypyridine, hma = hexamethylenetetramine, bza = benzamide, nia = nicotinamide, ina = isonicotinamide, cbz = carbamazepine, aca = acetamide, ppa = propionamide, bzamH+ = benzamidinium). Except for ctz-ppa and ctz-aca, all cocrystals were stable toward milling with 1 weight equiv PVP or MCC. It was also shown that the cocrystals ctz-bipy, ctz-ebipy, ctz-pbipy, ctz-pyr, ctz-hma, ctz-bza, ctz-ina, ctz-cbz, and the salt (bzamH+)(ctz-) formed in situ, when ctz was milled with the respective coformer in the presence of PVP or MCC. The stability and formation of ctz-cbz, ctz-nia, and htz-nia (htz = hydrochlorothiazide) toward grinding with a wider range of excipients (HPC, alpha-lactose, deoxycholic acid, and sodium taurocholate) was also investigated, and the results are discussed with regard to the heterosynthons of the ctz cocrystals and competing H bonding with the excipients.