1. Crystallization Conditions and MSZW of Memantine Hydrochloride Kiomars Karami 1, Patrick Hughes 1 and Scott Smith 1 Physical Chemistry, Pharmaceutical Development 1, Allergan, Inc., Irvine CA MATERIALS The MSZW is defined as an excessive super- saturation, or anti-solvent composition, at which the number density of primary crystal nuclei has reached equilibrium. The MSZW reflects the nucleation characteristics of a system and is considered to be useful in exploring crystallization. 1 The super saturation concentration, temperature, solvent/anti- solvent, cooling and heating rate are components that have impact on crystallization and formation of polymorphs. 1,2 Memantine is a relatively new drug with pharmacological property as an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. 3 The hydrochloride salt of memantine is a selected form that has shown no tendency to polymorphism. Crystallization condition and MSZW for memantine hydrochloride in several polar and medium polar solvents, i.e. water, methanol, acetic acid and a methanol/ethyl acetate mixture were studied at small scale applying heating and cooling of the drug at super-saturated concentration in the above mentioned solvents followed by solvent evaporation at a high vacuum and ambient temperature. INTRODUCTION The purpose of this study was to evaluate the crystallization conditions and meta-stable zone width (MSZW) of memantine hydrochloride (MemHCl) for optimum crystallization in polar and medium polar solvents at different concentration and temperature using the heating/cooling control followed by solvent evaporation at high vacuum. PURPOSE The metastable zone width (MSZW) of memantine hydrochloride was determined at small scale by Crystal-16 crystallization equipment utilizing controlled thermo-cycling at different concentration of the drug in the above mentioned solvents (Class 2 and Class 3). Rigaku powder X-ray diffractometer (XRPD) was used to screen crystalline form of re- crystallized MemHCl. A Thermo-Scientific fourier transform infrared spectrometer (FTIR) was used to confirm the chemical ID of the crystallized MemHCl by comparing the samples to a MemHCl reference standard. A gas chromatographic (GC) method was used to determine the amount of residual solvents in re-crystallized MemHCl samples. Results from the heating/cooling experiments by Crystal 16 indicated the precipitation points (in °C) at different concentrations (in mg/mL). The data suggested that the best solvent for crystallization is methanol (MSZW below 30°C, which is close condition to the ambient temperature). Figures 1-4 are presenting the MSZW of MemHCl in different solvents as a result of the thermo-cycling events. Methanol is the most suitable solvent for crystallization of memantine hydrochloride at small scale. MSZW indicated a super saturation concentration rang of 300-365 mg/mL for the drug in methanol. Crystallization of memantine hydrochloride from methanol solutions is sufficient by using a solvent evaporation process at ambient temperature and high vacuum. CONCLUSIONS REFERENCES 1. An interpretation of the metastable zone width concerning primary nucleation in anti-solvent crystallization: Noriaki Kubota, Journal of Crystal Growth: 310 (2008) 4647–4651. 2. A new interpretation of metastable zone widths (MSZW) measured for unseeded solutions: Noriaki Kubota, Journal of Crystal Growth: Vol. 310 (2008) 629-634. 3. Mechanism of action of memantine: Jon W Johnson et. al. Current Opinion in Pharmacology 6 (2006) 61–67. RESULTS Table 1. Effect of methanol activity on precipitation temperature of Memantine Hydrochloride in methanol/ethyl acetate mixture. Figures 5. XRPD patterns of Memantine Hydrochloride crystallized in water, methanol, acetic acid and methanol/ethyl acetate. XRD Conditions: diffraction angles 2-50°(2  , step size 0.02°(2  counting time 1.8 sec/step. Figures 6. FTIR Spectra of Memantine Hydrochloride crystallized in water, methanol, acetic acid and methanol/ethyl acetate. METHODS Methanol Activity Precipitation Temp. (ºC) Dissolution Temp. (°C) 0.9516.424.6 0.9024.929.6 0.8525.832.9 0.8033.937.6 The organic solvents used in this study; methanol, acetic acid and ethyl acetate manufactured by Fluke and Sigma-Aldrich were provided from VWR. Memantine hydrochloride was provided from Lundbeck Pharmaceutical, Italy. Following is the molecular structure of Memantine Hydrochloride: Figures 4. MSZW of Memantine HCl in methanol/ ethyl acetate at concentration of 375 mg/mL and different methanol activity (0.80-0.95). Figure 2. MSZW of the Memantine Hydrochloride in water (heating from 5°C to 95°C at 0.3°C/min, cooling from 95°to 5°C at 0.3°C/min) Solvent evaporation at ambient temperature and high vacuum resulted in needle shaped crystals (acicular habit) consistently. Following is a SEM image of the MemHCl crystals: Figure 1. MSZW of Memantine Hydrochloride in methanol (heating from-5°C to +65°C at 0.3°C/min, cooling from 65°to 5°C at 0.3°C/min) Figure 3. MSZW of the Memantine Hydrochloride in acetic acid (heating from 5°C to 80°C at 0.3°C/min, cooling from 80°to 5°C at 0.3°C/min) Table 2. Residual solvent in Memantine Hydrochloride samples crystallized in methanol and methanol/ethyl acetate mixture compared to the Ref. Std. Figure 4 and Table 1 presents effect of the methanol activity on precipitation of MemHCl in the methanol/ethyl acetate mixture (cloud point determined by turbidity measurement). The effective methanol activity at ambient temperature shown to be 0.9 (v/v%) The XRPD analysis of the crystallized MemHCl samples showed that the drug substance consistently forms one identical polymorph when crystallized in water, methanol, acetic acid and methanol/ethyl acetate mixture by thermo-cycling followed by solvent evaporation at high vacuum and ambient temperature. Acknowledgment: Technical support by Ms. Christina Do and Dr. Kevin Krock at Allergan Analytical Sciences in determination of the residual solvents by GC chromatography is sincerely acknowledged. The level of residual solvents in MemHCl recovered from methanol and methanol/ethyl acetate mixture (assayed by GC) is compared to a MemHCl standard in Table 2.