Confused HCl: Hydrogen Chloride or Hydrochloric Acid?

Hydrogen chloride (HCl) is a gas under standard conditions. HCl has been commonly used, either in the gaseous form or as solutions, for many applications, such as synthesis of both organic and inorganic compounds, salt formation, pH control and neutralizations, and surface cleaning. Hydrochloric acid is an aqueous solution of HCl (pKa = 6), with the formula of HCl ACHTUNGTRENNUNG(H2O)x (x decreases with increasing concentration of HCl). Despite the fundamental differences in both chemical compositions and physical states between them, the abbreviation “HCl” is commonly misused to represent hydrochloric acid while HCl solutions in other solvents have been rarely discussed. This misuse is found in chemistry textbooks. The confusion in the terminology also persists well into the current literature, including peerreviewed journals and common reference sources. Herein, we highlight the need of clarifying the confusion by showing the distinct behaviors of other forms of HCl and HCl ACHTUNGTRENNUNG(H2O)x in solid-state protonation of several common compounds. In recent years, the design, synthesis, and prediction of new solid-state structures have gained enormous interest because of fundamental, practical, and legal interests. Efforts by researchers around the world, under the umbrellas of crystal engineering, supramolecular chemistry, and solidstate chemistry, have led to significant progress in the synthesis of novel functional materials and successful crystal structure predictions. Hydrochloride salts are used in various branches of science ranging from chemical synthesis, to separation, and to pharmaceuticals. For example, it is estimated that over half of the medicines on the market are administered as salts, out of which, more than half of the salts of basic drugs are hydrochlorides. Perhaps because of both the wide availability of HClACHTUNGTRENNUNG(H2O)x in common laboratories and the confusion in the terminology, synthesis of hydrochloride salts is usually attempted using HCl ACHTUNGTRENNUNG(H2O)x instead of other forms of HCl. This practice generally leads to difficulty in the formation of hydrochloride salts of poorly ionizable bases. For example, solid-state protonation of carboxamide (or amide), weakly basic N-heterocycles functional groups, have been declared to be extremely difficult, if not impossible. Moreover, an estimated 30 % of APIs are considered non-ionizable in the solid state, for which salt formation has been generally excluded as a possible approach for solving drug delivery problems. However, since HCl can form a superacid when dissolved in suitable solvents, we hypothesize that solid-state protonation (or salt formation) of even poorly ionizable bases is possible by using HCl organic solutions other than HCl ACHTUNGTRENNUNG(H2O)x. An added advantage of using HCl organic solutions is the ability to prepare anhydrous HCl salts and the possibility of screening for their polymorphs. Carbamazepine (CBZ, Scheme 1) is a urea derivative drug for treating epilepsy and trigeminal neuralgia. Because of its importance in health care, extensive research