## 4 Discussion  
The published crystal structures containing the BP risedronate include its \"free\" forms and its metal-containing forms. The \"free\" forms include risedronic acid monohydrate [19; 26], the dihydrate [27], and the ammonium dihydrate [27]. The RIS derivatives that incorporate some kind of metal ion include the Na dihydrate and 2.5 hydrate [19], the K dihydrate [27], the Mg, Ni, and Fe coordination polymer derivatives [28], the Cu and Ni molecular complex derivatives [29] and a Cd coordination polymer [30]. With this paper, two more metal derivatives of RIS are added to the above list: the Ca- and Sr-RIS compounds. In this section, we discuss the behavior of the Ca- and Sr-RIS systems as controlled release agents. The controlled release curves of all systems studied here are shown in Figures 9 and 10. As shown above, the utilization of cationic organic additives (PAMAM-2 dendrimer and LPEI polymer) was necessary to avoid bulk crystallization of the released RIS into the acidic medium. The results obtained here show that the metal-containing RIS systems exhibit higher initial release rates than the \"free\" RIS system (no metals). This observation is in contrast to what was observed before in our previous work [11] for other BP drugs, in which the \"free\" drug was released much faster than the metal-containing drugs. The results obtained herein appear to be counterintuitive because the \"free\" RIS is released much more slowly than in the Ca-RIS and Sr-RIS systems. The latter systems need to overcome the acid hydrolysis of the metal-O bond in order to release RIS. In this section, we attempt to interpret the drug release results based on the various interactions noted in the solid state of RIS monohydrate, Ca-RIS and Sr-RIS. The slow initial rate for the \"free\" RIS may be related to the stability of the crystal lattice of the compound. The water solvent must overcome several stabilizing interactions. There are strong \(\pi\)-\(\pi\) interactions between the pyridyl rings (centroid-to-centroid distance 3.487 A). These are hydrophobic interactions, so the solvent (water) cannot penetrate the crystal lattice and \"break\" them. The presence of one lattice water further stabilizes the crystal structure because hydrogen bonds are formed with the phosphonate groups. The phosphonate groups of RIS form nine hydrogen bonds overall. The Ca-RIS compound can be described as a 1D coordination polymer, propagated by Ca-O(phosphonate) bridging. There are weak \(\pi\)-\(\pi\) interactions between the RIS pyridyl rings since the centroid-to-centroid distance is very long (5.340 A). There are three H-bonding interactions (per molecular unit) between the chains (Figure 5b,c). This means that the chains can be easily penetrated by the water solvent and the Ca-O bonds can be effectively hydrolyzed in the acidic medium. The Sr-RIS compound is a 2D coordination polymer. This compound presents the fastest initial rate. Careful examination of its crystal structure reveals that the layers are  
Figure 10: RIS release curves from Ca- and Sr-RIS containing tablets and comparison with the “free” RIS system. The experiments were performed in the presence of LPEI at pH = 1.3.  
not stabilized by H bonding, and for that reason, they can be readily exfoliated by the water solvent. Thus, the Sr-O bonds are exposed to the acidic medium and could be easily hydrolyzed. Nevertheless, there are \(\pi\)-\(\pi\) interactions between the RIS pyridyl rings (centroid-to-centroid distance 3.837 A) (Figure 6b), but based on the centroid-to-centroid distance, they are weaker than those in the structure of \"free\" RIS. It is interesting that the pyridyl rings are not exactly parallel to each other, and this \"tilting\" may further weaken these interactions. The Ca-RIS system displayed a somewhat slower RIS release than the Sr-RIS system (0.44 umol/min vs. 0.52 umol/min). The Ca-O bond distances are shorter (average 2.416 A) than the Sr-O bond distances (average 2.643 A).