New multicomponent crystal forms of adiphenine with low hygroscopicity.

Abstract

Adiphenine is an acetylcholine receptor inhibitor used as an antispasmodic drug due to its strong smooth muscle relaxant action. Adiphenine hydrochloride is largely marketed in drug associations to treat muscle spasms and relieve pain in colic and cramps. However, it presents serious problems with hygroscopicity and chemical stability under high humidity conditions, which have limited its use as an active pharmaceutical ingredient (API). Here, we have solved the adiphenine solid-state hygroscopicity problem through the preparation of stable, nonhygroscopic multicomponent crystal forms thereof. Two new salts of adiphenine were designed by recognition of intermolecular interaction patterns in the Cambridge Structural Database (CSD) and ΔpKa rules. Two generically recognized as safe (GRAS) coformers, namely, citric acid and oxalic acid, were chosen and formed monobasic salts with adiphenine. Crystal structure elucidation reveals that adiphenine adopts different conformations in our salts, while in the literature, hydrochloride adopts one, which is related to different intermolecular arrays. In the dynamic vapor sorption (DVS) analysis, it was verified that adiphenine citrate and adiphenine oxalate starts to incorporate water slowly from 50 to 70% of relative humidity (RH), increasing up to 3.2 and 2.6% of their initial masses in 90% of RH, respectively. At the end of the desorption cycle (RH = 0%), the samples retained only 0.12 and 0.08% of water relative to their initial masses. On the other hand, adiphenine hydrochloride exhibits a classical high hygroscopicity behavior, which retains water fast from 50% of relative humidity (RH), increasing up to 22% of its initial mass in 90% of RH and a net mass gain of 5% at the end of the desorption cycle (RH = 0%). Notably, both carboxylic acid salts had similar solubility as a function of medium pH, while the hydrochloride one was more soluble than them by factors ranging from 6.7 (relative to citrate in pH 1.2) to 28.2 (relative to oxalate in pH 4.5). Nevertheless, the pharmacokinetic parameters of adiphenine after oral administration of the capsules containing the salt forms did not reflect these solubility differences, since all adiphenine salt forms can be considered highly soluble drugs according to the Biopharmaceutics Classification System (dose/solubility ratio < 250 mL). It was observed that the rats treated with capsules containing adiphenine hydrochloride had an increase in AUC0−∞ (1537 vs 914 vs 991 min μg mL−1

) compared with rats treated with adiphenine citrate and oxalate capsules, respectively, even though the same tmax (48 min) was observed. However, dosage tuning can bring the bioavailability of our salts into that of the hydrochloride salt, with the advantage of nonhygroscopicity and higher chemical stability.