Drug-Drug Multicomponent Crystals as an Effective Technique to Overcome Weaknesses in Parent Drugs Okky Dwichandra Putra, † Takayuki Furuishi, § Etsuo Yonemochi, § Katshuhide Terada, ‡ and Hidehiro Uekusa* ,† † Department of Chemistry and Materials Science, Tokyo Institute of Technology, Ookayama 2-12-1, Meguro-ku, Tokyo 152-8551, Japan § School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41, Ebara, Shinagawa, Tokyo 142-8501, Japan ‡ Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan * S Supporting Information ABSTRACT: An interesting multicomponent crystal consisting of drug-drug combination was synthesized. The multidrug crystals consisted of antidiabetic drugs glicalzide and metformin. Single crystal X-ray structure analysis revealed that this multicomponent crystal is salt-type multicomponent crystal. The physicochemical properties of this crystal were significantly different from those of the parent drugs. The multicomponent crystal showed impressive solubility and dissolution rate compared to that of the raw material of gliclazide. Also, the hygroscopicity issue in metformin was tackled by the formation of multi- component crystal. These physicochemical property alterations were associated with the existence of hydrophilic channel structure, which was confirmed by microscopic analysis. Therefore, the weaknesses of each component were mutually solved. T he preparation of multicomponent crystals, i.e., cocrystals, salts, solvates, and hydrates, is a well-established technique for forming new phase(s) and altering the physicochemical properties of drug materials. 1-9 Interestingly, recent studies have investigated the potential of multicomponent crystals containing combinations of drugs. 10-15 This family of crystals, in addition to providing technological advantages, also offers improved pharmacological benefits and patient compliance. 16,17 These are likely the most important advantages of drug-drug multicomponent crystals compared with single drug and nondrug multicomponent crystals. Screening of marketed combination drug formulations yielded the combination of the non-insulin-dependent diabetes mellitus (NIDDM) drugs metformin (MET) and gliclazide (GLI). MET (N-1,1-dimethylbiguanide) is a derivative of a blood glucose normalizing compound of guanidine, and GLI (1-(1-azabicyclo-[3,3,0]-oct-3-yl)-3-(p-tolyl sulfonyl) urea) is a potent oral hypoglycaemic agent for long-term treatment of diabetes mellitus. 18-20 MET and GLI are effective in the treatment of NIDDM in both single and combined therapies. Recently, combination oral therapies have become more widely used and medically necessary. Indeed, the combination of MET and GLI provides better results regarding glycemic control and the lipid index, which are often major problems during the treatment of diabetes. 21 Unfortunately, both MET and GLI exhibit unfavorable physicochemical properties. The base form of MET is a hygroscopic powder. 22 Attempts to overcome this hygro- scopicity, such as special treatment during the manufacturing process and the use of a closed packaging system, are expensive and may increase the cost of the drug. 23 Thus, in order to avoid hygroscopicity, MET is commercially available as a hydro- chloride salt. 24,25 In addition, GLI, a class II molecule according to the Biopharmaceutical Classification System, exhibits low solubility. 26 Micronization, complexation with β-cyclodextrin, and formation of solid dispersions have been used to attempt to improve the solubility of GLI. 27-29 Unfortunately, these above- mentioned methods for improving the physicochemical proper- ties of MET and GLI are difficult to control reliably. The preparation of multicomponent crystals is a highly advanced technique that can be used to alter the physicochemical properties of drugs by rearranging the molecules to form a new crystal structure. 30 By controlling how molecules interact, analysis of changes in physicochemical properties will be further simplified, representing the major advantage of multicomponent crystals. 31 In this study, we prepared novel multidrug crystals consisting antidiabetic drugs of GLI and MET. We also performed structural analyses of these crystals. Additionally, we describe molecular insights derived from crystal structure into changes in the physicochemical properties of MET and GLI. Although the single phase multicomponent crystal of MET and GLI could also be obtained from liquid assisted grinding and ball milling, we used the solvent evaporation technique to grow single crystals (Figure 1). Interestingly, “halo” peaks were Received: April 26, 2016 Revised: June 16, 2016 Published: June 17, 2016 Communication pubs.acs.org/crystal © 2016 American Chemical Society 3577 DOI: 10.1021/acs.cgd.6b00639 Cryst. Growth Des. 2016, 16, 3577-3581