Antihistamine compounds in the form of their free bases as well as their salts, e.g. hydrochloride, maleate, tannate, etc. are well known. Frequently, it is desirable to utilize the antihistamine in the form of its tannate salt, because such salt is generally quite stable and may be administered in such form without any untoward side effects. Tannic acid, also known as tannin, is a well known naturally occurring substance. Commercially available tannic acid usually contains about 5 wt. % water, has a molecular weight of about 1700 and is typically produced from Turkish or Chinese nutgall.
Commercially available antihistamine tannate compositions are relatively impure. Such compositions are typically prepared by reacting the antihistamine free base with tannic acid in the presence of a volatile solvent, usually isopropanol. The yield is only fair (e.g. about 70%) and decomposition products e.g. 2-5 wt. %, and a significant amount of the volatile solvent, e.g. 6-10 wt. %, based on the weight of the composition, remains with the product and cannot be removed.
Typically, in the conventional isopropanol route, the antihistamine free base and the tannic acid will be present in the isopropanol at a concentration of about 20 wt. %, based on the weight of the reaction mixture. The reaction mixture is stirred for about one hour, while maintaining a temperature of 60.degree.-70.degree. C. The reaction mixture is cooled to room temperature and filtered. The precipitate is vacuum dried for an extended period of time at a temperature of 60.degree.-80.degree. C. A yield of product of only about 70% is obtained and the product purity will be about 85-90 wt. %, based on the weight of the composition (the impurities consist of isopropanol and decomposition products which cannot be removed).
Many antihistamine tannates, e.g. phenylephrine tannate, are heat sensitive and therefore undergo decomposition quite readily upon prolonged exposures to temperatures as low as 50.degree. C. Accordingly, even when the solvent utilized in its preparation has a relatively high vapor pressure such as is in the case of isopropanol, it is impossible to reduce the solvent content below about 6 wt. %, based on the weight of the antihistamine tannate composition, even at reduced pressures and very mild elevated temperatures. Moreover, from an environmental point, it would be most desirable if the antihistamine tannate could be prepared such that the use of volatile solvents could be avoided.