Lamivudine Salts with Improved Solubilities FELIPE T. MARTINS, 1 RUDY BONFILIO, 2 MAGALI B. DE ARA ´ UJO, 2 JAVIER ELLENA 3 1 Instituto de Qu´ ımica, Universidade Federal de Goi´ as, Campus Samambaia, Goiˆ ania, Goiˆ as, Brazil 2 Centro de Equivalˆ encia Farmacˆ eutica do N ´ ucleo Controle de Qualidade da Universidade Federal de Alfenas, Universidade Federal de Alfenas, 37130-000 Alfenas, Minas Gerais, Brazil 3 Instituto de F´ ısica de S˜ ao Carlos, Universidade de S˜ ao Paulo, 13560-970, S˜ ao Carlos, S˜ ao Paulo, Brazil Received 12 December 2011; revised 6 February 2012; accepted 23 February 2012 Published online 14 March 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23117 ABSTRACT: To optimize solubility of drugs, current strategies mainly focus on engineer- ing and screening of smart crystal phases. Two salts of the anti-human immunodeficiency virus (HIV) drug lamivudine—namely, lamivudine hydrochloride and lamivudine hydrochlo- ride monohydrate, were prepared in the course of screening the crystallization conditions of lamivudine duplex, an uncommon DNA-mimic, double-stranded helical structure made up of partially protonated drug pairs. Here, water solubilities of lamivudine hydrochloride, lamivu- dine hydrochloride monohydrate, and lamivudine duplex are reported. The aqueous solubility of this anti-HIV drug was significantly increased in both salts and also in lamivudine duplex in relation to the water solubility of lamivudine form II. In comparison with the lamivudine form II incorporated into therapeutic formulations, the drug solubility was increased at a tem- perature of 299 ± 2 K by factors of 1.2, 3.3, and 4.5 in lamivudine hydrochloride, lamivu- dine hydrochloride monohydrate, and lamivudine duplex, respectively, demonstrating that this solid-state property of lamivudine can be improved by crystal engineering strategies. Solu- bility profiles were understood on the basis of structural and solvent–solute interaction ap- proaches. At last, correlations between solubility and crystal structures allowed for a rational approach to understand how this physicochemical feature could be enhanced by engineering new salts of the drug. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2143–2154, 2012 Keywords: crystal structure; solubility; structure–property relationship; pseudopolymor- phism; crystal engineering; single-crystal X-ray diffractometry; lamivudine; hydrochloride salts; nucleoside duplex; anti-HIV drugs INTRODUCTION Drug development includes various steps beginning from discovery of a biologically active molecule to ap- proval of an active pharmaceutical ingredient (API) for marketing. As part of the drug development pro- cess, bioavailability handling is a challenge for a potential drug to become a marketable API. Some- times, drug development of potentially active com- pounds with highly desirable pharmacodynamical profiles does not forward because of their undesir- able physical behaviors responsible for unfavorable bioavailability. 1,2 Adequate manufacturing proper- ties and shelf life are also intended to a developable Correspondence to: Felipe T. Martins (Telephone: +55-62-3521- 1097; Fax: +55-62-3521-1167; E-mail: felipe@quimica.ufg.br) Journal of Pharmaceutical Sciences, Vol. 101, 2143–2154 (2012) © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association compound. 3 Furthermore, a stable solid-state phase of a drug candidate compound is preferred over an- other unstable or fluid one because most APIs are administered into pharmaceutical solid dosage forms for practical and easy way of storing and intake of drug products. 3 All these requirements should be sat- isfied preferentially without changing drug molecular framework related to certain pharmacological action. Therefore, one can see that introducing an API into market is quite beyond certifying its therapeutic ef- fect on a biological target system. One way to alter and control bioavailability con- sists of changing the physicochemical properties of a drug by modifying its solid-state features. 4–6 Among all solid-state properties of a drug, solubility is di- rectly related to its bioavailability. 7,8 To optimize solubility of APIs, current strategies mainly focus on engineering and screening of crystal phases. 9–15 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 6, JUNE 2012 2143