Solid-State Phase Transition Mechanism and Physical–Chemical Study of the Crystal Forms of Monosodium Alendronate: Trihydrate versus Anhydrate

Abstract

Alendronic acid is one of the most effective diphosphonate compounds used for clinical treatment of bone disorders. It is administered orally as its monosodium salt, for which hydrate and anhydrous crystal forms are known. The monosodium alendronate trihydrate form (NaH 4 A•3H 2 O) is incorporated into medicines as the Active Pharmaceutical Ingredient (API). The NaH 4 A•3H 2 O form can be dehydrated at temperatures above 115 °C, resulting in the anhydrous form (NaH 4 A). Although the crystal structures of both forms have already been reported, an investigation of the reversible dehydration/hydration solid-phase transition is presented here for the first time. A solid-state mechanism for the phase transition, which involves the reversible dehydration−hydration of the NaH 4 A•3H 2 O and NaH 4 A forms, is also proposed. A systematic study comparing the equilibrium solubility and discriminatory intrinsic dissolution of the NaH 4 A•3H 2 O and NaH 4 A forms is included. To achieve this goal, an alternative method of quantifying alendronate anions released from the crystal forms into solution, flame photometry, is proposed and validated. The stability and interconversion of the NaH 4 A•3H 2 O and NaH 4 A forms are probed by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy−attenuated total reflectance (FTIR-ATR), and powder X-ray diffraction (PXRD).

Polycaprolactone/alendronate systems intended for production of biomaterials

“…PCL presented an endothermic transition around 63.23°C, which is in agreement with what is reported in the literature 37,55,56 . The DSC curve of ALD exhibits two endothermic peaks, at approximately 125 and 130°C (Figure 5), which is in agreement with the literature 57 . These peaks are related to the dehydration process, as observed in the TG curve (Figure 3), with a mass loss of 16%.…”

“…These peaks are related to the dehydration process, as observed in the TG curve (Figure 3), with a mass loss of 16%. According to Gonzaga et al ., 57 this double event, also showed in Figure 4, is associated to the release of non‐coordinate and coordinate water molecules present in the crystal structure of ALD trihydrate. The two water molecules that are non‐coordinated to the sodium cation are released first, at approximately 125°C, followed by the coordinated molecule, at 130°C, which is more strongly bonded.…”

Pharmaceutical Hydrates Analysis—Overview of Methods and Recent Advances

“…Another crucial aspect for the industry is spontaneous water absorption. In such a process, anhydrate carbamazepine converts into the hydrate form I, whose different crystallinity leads to a significant decline of the drug’s bioavailability [ 142 ]. An adverse process is of no less importance as some APIs undergo water desorption-induced phase transition.…”

Investigation of Physical Properties of Disodium Etidronate Tetrahydrate and Application of Phosphorus K-Edge X-Ray Absorption Near-Edge Structure Spectroscopy

“…Bisphosphonates inhibit osteoclastmediated bone resorption and are widely used in the treatment of bone disorders such as osteoporosis and Paget's disease (1). The physical properties of some solid-state forms of bisphosphonates other than disodium etidronate have been reported, for example, of sodium alendronate (2,3), sodium ibandronate (4), and sodium risedronate (5). Although the crystal structure of disodium etidronate tetrahydrate had been reported as the solid-state form of disodium etidronate (6), details of the physical properties of disodium etidronate, including crystalline phase transformation, amorphization, desolvation, and moisture absorption remain unknown.…”