(T0930-01-01) Solid-State Properties and Phase Behaviors of Ephedrine Cyclamate

Purpose: Ephedrine is a compound used for the treatment of bronchitis and asthma. However, it is a bitter drug with extremely low tabletability. Therefore, a new salt of ephedrine, ephedrine cyclamate (Eph-Cyc), was prepared by reacting Ephedrine hydrochloride with an artificial sweetener, sodium cyclamate, to overcome these issues faced with ephedrine. We also investigated unusual phase behaviors between two polymorphs of Eph-Cyc using thermal and microscopic techniques.

Methods: Eph-Cyc was prepared by cooling a 72° C solution of ephedrine hydrochloride (Eph HCl, 0.2 gm) and sodium cyclamate (NaCyc, 0.2 gm) in 25 mL of distilled water. Thin plate-like crystals were formed. Single crystal X-ray diffraction was carried out using Bruker Photon-II CMOS diffractometer at 150 K with Mo radiation. The crystal structure was solved using SHELXTL. The phase purity of the bulk sample was evaluated using powder X-ray diffraction. Moisture sorption isotherm was obtained using a dynamic moisture balance. Mechanical properties of Eph-Cyc and its parent compounds, including the in-die P_y and tabletability, were characterized using a compaction simulator (Styl’One). Hot-stage microscopy (HSM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) were used to characterize the thermal properties of the polymorphs.

Results: Ephedrine cyclamate crystallizes in the orthorhombic P bca group with eight asymmetric units in one unit cell (a = 9.3623 Å; b = 14.4869 Å; c = 26.0845 Å). Each asymmetric unit contains one Eph⁺ cation and one Cyc^- anion (Figure 1). This is designated form I polymorph. Based on the P_y values (62.4 MPa for Eph-cyc, 86.8 MPa for Eph-HCl, and 108.3 MPa for Na-Cyc). Eph-Cyc is more plastic than both parent compounds. This results in improved tabletability of Eph-Cyc over Eph-HCL and Na-Cyc (Figure 1a). In fact, no tabletability profile could be generated for Eph- HCl since it failed to produce intact tablets. The better tabletability of Eph-Cyc is attributed to its better compressibility (Figure 1b) since its compactibility is not significantly different from Na-Cyc (Figure 1c). DSC data suggests that a new polymorph of Eph-Cyc (form II) is formed on heating form I to 165° C. Using HSM, the I → II transition of Eph-Cyc upon heating was visually confirmed. However, form I crystals sometimes melted without converting to form II or melted simultaneously with I → II conversion. The probability of I → II solid-state transformation increases with increasing crystal size. Moreover, the kinetics of the I → II transition also depends on the heating rate (Table 1), where 20-25° C/min was the optimal heating rate. Form II melts at about 180° C, accompanied by simultaneous dissociation into ephedrine (free-base) and cyclamic acid. The latter forms S, N and O oxides at 270° C, leading to significant weight loss in the TGA thermogram. DSC data clearly showed that form II converts to I on cooling under hermetically sealed conditions, which converts back to II at 155° C upon the second heating (Figure 2a). However, the production of bulk form II using various thermal techniques simulating the heating and cooling cycle in DSC was unsuccessful. Further examination revealed that the Form II to I transition is sensitive to pressure since it could not be observed when pressure built-up was eliminated by using a DSC pan with a pinhole (Figure 2b).

Conclusion: A new 1:1 salt, ephedrine cyclamate, was produced using an ion exchange reaction between ephedrine HCl and sodium cyclamate. The Eph-cyc salt displayed higher plasticity and improved tabletability than its parent compounds. Two polymorphs are enatiotropically related with a transition temperature lying between 50° C and 150° C. The interconversion kinetics between the two polymorphs depends on temperature, heating rate, crystal size, and pressure.

References: 1. Vreeman G, Sun CC. Mean yield pressure from the in-die Heckel analysis is a reliable plasticity parameter. Int J Pharm X. 2021;3:100094. doi:https://doi.org/10.1016/j.ijpx.2021.100094
2. Medina DA V, Ferreira APG, Cavalheiro ETG. Polymorphism and thermal behavior of sodium cyclamate. J Therm Anal Calorim. 2019;137:1307-1313.
3. Sun CC, Hou H, Gao P, Ma C, Medina C, Alvarez FJ. Development of a high drug load tablet formulation based on assessment of powder manufacturability: moving towards quality by design. J Pharm Sci. 2009;98(1):239-247

Table 1. Statistics of Form I → II conversion at different heating rates.

Figure 1. a) Tabletability, b) Compressibility, c) Compactibility profiles of Eph-Cyc and Na-Cyc. Eph-HCl is not shown here because intact tablets could not be prepared.

Figure 2. DSC thermograms of Eph-Cyc using a hermetically sealed pan; a) without a pinhole, b) with a pinhole.