Effects of Temperature and Relative Humidity on the Solid-State Chemical Stability of Ranitidine Hydrochloride

Effects of Temperature and Relative Humidity on the Solid-state Chemical Stability of Ranitidine Hydrochloride REIKOTERAOKA, MAKOTO OTSUKA, AND YOSHlHlSA MATSUDA' Received September 13, 1991, from the Department of Pharmaceutical Technology, Kobe Women's College of Pharmacy, Motoyama-Kitamachi 4-191,Higashi-Nada, Kobe 658,Japan. Accepted for publication October 26, 1992. injector (model 712, Waters Associates), integrator (model 820, Waters Associates), and variable-wavelength U V absorbance detector (model 484, Waters Associates) operated at 314 nm. The prepacked column (LiChrospher RP-18, 5 pm; 125 x 4 mm ID, Merck) was operated at 30 "C at a flow rate of 0.8 mWmin. The mobile phase consisted of a solvent system of methano1:O.l M ammonium acetate degradation in the unbuffered solution increased dose dependently. The (17:3).A benzalphthalide solution (1mg/mL) was used as an internal critical relative humidity (CRH) of the ranitidine HCI bulk powder was standard. After the storage experiment, 3 mL of the internal standard -67% relative humidity (RH). The amount of water adsorbed onto the solution was added to the sample, and the mixture was diluted 60 sample above the CRH was proportional to the RH level. The percent times with methanol. Two microliters of the sample solution was degradation of the powder below 50% RH was almost negligible injected into the chromatograph to determine the concentration of because, at this level, it was a solid. The percent degradation at 60-70% unchanged ranitidine HCl. RH was higher than that above 70% RH. Ranitidine HCI powder was Chemical Stability Study in Solution-The effect of the pH of the unstable around the CRH. aqueous solution on chemical stability of the drug was investigated as follows. One hundred milligrams of the drug were dissolved in 10 mL of 0.1 M acetic acid buffered solutions at various pH values (ionic strength, 0.1; pH 4.01,5.01, and 6.18). Capped tubes (4 mm diameter, The interaction of water with powdered materials is a major 40 mm length) containing 300 pL of sample were stored at 65 "C. The concentration of drug remaining was determined by HPLC. fador in the formulation, processing, and product perforThe effect of the drug concentration in solution on chemical mance of solid pharmaceutical dosage forms.1 The effects of stability was investigated as follows. The drug was dissolved in environmental conditions on the solid-state chemical stabildistilled water at various concentrations (1.3, 13.0, and 69.4 w/w%). ity are therefore important considerations in the design of Experimental procedures were the same as described in the previous pharmaceutical preparations.2 To improve drug stability in section. dosage forms, many researchers have investigated the deSecondary-Ion Mass Spectrometry (SIMSHIMS spectra were composition kinetics of drugs in the solid state (e.g., aspiobtained with a M-4100 type mass spectrometer (Hitachi Company, rin,3-6 propantheline bromide,e glutathione,7 and niJapan) with glycerol as a matrix. The mass spectra of the samples trazepams). were measured without purification &er storage. Chemical Stability in the Solid State-Glass bottles (5 mL) The hydrochloride of a drug is the most popular compound containing 5 mg of sample powder were stored in polystyrene bottles salt because of its ease of crystallization and high solubility. containing saturated aqueous solutions of the various salts at 50,60, However, some hydrochlorides are highly hygroscopic0 and 70, 85, 96, and 100% RH at 45, 55, and 65 "C. After storage, the unstable. The critical relative humidity (CRH) of pilocarpine amount of ranitidine HC1 remaining was determined by HPLC. HCl at 37 "C is 59%, that of diphenhydramine HC1is 77%, and Measurement of Water Content-After 2 h of storage at various that of thiamine hydrochloride is 88%. Meclofenoxate HCl temperatures and RHs, the water content in the 5-mg samples was was unstable at high humidity.10 measured by the Karl-Fisher method (model MKA-3, Kyoto Denshi Ranitidine HC1(N-[2-{5-[(dimethylamino)methyllfurfuryl}- Company, Japan). Measurement of CRH-Twenty microliters of distilled water were thio)ethyll-N-methyl-2-nitro-l,l-ethenediamine hydrochloplaced into dry bottles containing 100 mg of ranitidine HC1 powder. ride) is a histamine H,-receptor antagonist that is widely used The bottles were stored at 50,60,75, and 85% RH and at 45,55, and as an antiulcer agent. The commercial solid dosage forms are 65 "C for 2 h, and the water content was estimated from the weight not stable against humidity,ll so they are required to be strip loss or gain. packaged. Uzunarslan and Akbugal2 reported on the hygroAbstract 0 The chemical stability of ranitidine HCI in solution and in the solid state at various temperatures was investigated by highperformance liquid chromatography. Ranitidine HCI was unstable in lower pH buffer solutions, and the percent degradation after 72 h increased as the pH of the buffer solution was reduced. The percent

scopicity of a mixed powder of ranitidine HC1 and several additives and the effects on compaction properties. However, the stability of ranitidine HC1 bulk powder at various humidity and temperature levels has not been reported. We investigated the solid-state chemical stability of the drug at high humidity and temperature to provide basic information for pharmaceutical design of the preparation.

Experimental Section Materials-Ranitidine HC1 bulk powder (lot no. 10500) provided by Glaxo Japan Company Ltd. was dried under reduced pressure at 50 "C for 2 h before use. The specific surface area of the powder was 0.70 m2/gas measured by BET N, gas adsorption. All other reagents were of analytical grade unless otherwise stated. High-pressure Liquid Chromatography (HPLC) Analysish i t i d i n e HCl was analyzed with a HPLC system consisting of a solvent delivery system (model 510, Waters Associates), automatic

oO22-3549/93//060060 1$02.5G/O 0 1993, American Pharmaceutical Association

Results and Discussion Chemical Stability of Ranitidine HCl in Solution-Figure 1 shows the degradation profiles of ranitidine HC1 in various buffer solutions (10mg/mL) at 65 "C. The degradation processes showed sigmoid curves. No change was observed in buffer at pH 6.18after the degradation test, but the others changed from pH 4.01 and 5.01 to 4.47 and 5.32, respectively. These results suggest that the degradation of the drug followed a complicated kinetic mechanism. The percent decomposition after 72 h in storage was measured as a parameter to evaluate the stability of the drug. Figure 2 shows the relation between the percent decomposition (PD,,) estimated from the degradation curves in Figure 1 and the initial or final pH values. The PD,, at pH 4.01was 88.7%, whereas that at pH 6.18 was almost zero, indicating Journal of Phamceutical Sciences I 601 VO~. 82, NO. 6, June 1993

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Scheme I-Decomposition pathway of ranitidine HCI at lower pH.

Time, h Figure I-Degradation profiles of ranitidine HCI in 0.1 M acetate buffer solutions (ionicstrength = 0.1) at 65 "C. Key: (m)pH 4.01; (0)pH 5.01;

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Figure 2-Relationship between the percent degradation of ranitidine HCI after 72 h of storage and the pH of buffer solutions at 65 "C. Key: (0) pH of the initial buffer; (0)pH after 72 h. that ranitidine HC1 was unstable at lower pH and that the degradation rate increased. The SIMS spectra of the sample solutions after storing at pH 4.01 for 17 h and at pH 5.01 and 6.18 for 168 h were measured. The mass spectrum of the sample at pH 6.18 showed typical fragments m/z = 337 [M+Nal+ and mlz = 359 [M+2Nal+ due to the original drug, but no fragment larger than mlz = 359 [M+2Na]+. However, the spectra of the samples at pH 4.01 and 5.01 showed fragments due to the original drug plus new fragments mlz = 319 [M+Nal+due to 4 and n l z = 474 [M+Nal+, mlz = 496 [M+Nal+ due to 5, as shown in Scheme I. These results suggest that new adducts were formed after the secondary decomposition reaction. Intramolecular hydrogen bonding of ranitidine at the lower pH has been discussed by Geraldes et al.13 Scheme I shows the pathways of ranitidine HC1 decomposition at lower pH.14 The pathway suggested that the degradation reaction was initiated by protonation of ranitidine (1)and that ranitidine was degradated at lower pH. Furfuryl alcohol (2) and thiazine (3) were formed at first by the hydrolysis of ionized ranitidine. Thereafter, 2 r e a d with 1 or 3, and their adducts (4 and 5 ) were formed as secondary reactions. Thus, ionized ranitidine (protonated) is more labile than the un-ionized form. Therefore, the results suggest that ranitidine HC1 in aqueous solution is unstable at lower pH, and that the decomposition 602 I Journal of Pharmaceutical Sciences Vol. 82,No. 6, June 7993

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Figure %Degradation profiles of ranitidine HCI in distilled water at 65 "C.Key: (0)69.4 WW?; (A) 13.0 w/w%; (0)1.3 w/w%. did not follow apparent first-order kinetics because the reaction pathway was complex. Figure 3 shows the effect of the initial drug concentration on ranitidine HCl degradation in water at 65 "C. The percent decomposition increased at higher concentrations, indicating that the degradation rate depended on the drug concentration. The pH of 69.4,13.0,and 1.3 wlw% solutions changed from 4.8, 5.0, and 6.2to 6.9,7.3,and 6.9,respectively. The initial pH of the 69.4w/w% solution was lower than that at 1.3 wIw%, and the pH change of the former was larger than that of 1.3 w/w%. These results suggest that some degradation products affected the pH. Figure 4 shows the relation between PD,,, and the initial drug concentration and initial pH. The plot was a straight line at the initial pH, but the relationship between the PD192 and initial drug concentration was not linear, suggesting that the degradation at 69.4w/w% (nearly 60% saturation) was much faster than that at 1.3 w/w%. The Henderson-Hasselbalch equation (eq 1)indicated the ratio of the amount of the ionized to the un-ionized drug in the solution. Because the pK, (where K, is the acid dissociation constant) of ranitidine was 8.3815 the ionized drug dominated at the lower pH. pH

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It appeared that the concentration dependence of the drug stability in solution was related to the ratio of the ionized drug to the un-ionized drug.

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Relative humidity, % Figure +The effect of temperature on the water content of ranitidine HCI bulk powder after 2 h Of storage at various RHs. Key: (0)45 "C; (A) 55 "'; (O) 65 OC.

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Hygroscopicity of Solid-state Ranitidine HC1-Figure 5 shows the relationship between the weight loss or gain of ranitidine HCl and RH at various temperatures. The CRHs of the drug were estimated from Figure 5,and were -67% RH at all temperatures tested. This result suggests that the drug was decomposed in the solid state below the CRH, but as a liquid above the CRH. This also suggests that the CRH was independent of the temperature under these conditions. Figure 6 shows the effect of temperature on the water content of ranitidine HCl bulk powder after 2 h of storage at various RHs. Although the water contents of sample powders stored below 50% RH were within the experimental error (0.01%)and were -0.1% at 60% RH, those stored above the CRH (67%)adsorbed more water with increasing RH levels. Effects of RH and Temperature on the Chemical Stability of Solid State Ranitidine HC1-Figure 7 shows the effect of the RH on the degradation of ranitidine HC1 at 45 "C. No degradation was observed after 40 days at 50% RH, but the remaining drug content after 36 days at 60% RH was only 7%. The sample powder dissolved rapidly in the adsorbed water

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Time, h Flgure 7-The effect of RH on the degradation of ranitidine HCI bulk powder at 45 "C. Key: (0)50% RH; (0)60% RH; (0)70% RH; (A)85% RH; (H)96% RH; (A) 100% RH.

after storage at humidities above 70% RH, but the percentage remaining was higher than that a t 60% RH. This suggests that ranitidine HCl was stable below 50% RH as the powder, and the water absorption rate at levels above 75% RH was larger than that at 60% RH (Figure 6)but was susceptible to degradation at 60% RH rather than at levels above 75% RH (Figure 7).After the stability test, the sample powders were visually confirmed to have changed to the liquid state above the CRH, but not below 50%RH. It seems that below 50%RH the water molecules were adsorbed onto the crystal surface, whereas above 60% RH, the powder dissolved into a liquid. These results indicate that water above the CRH was actively involved in the decomposition, whereas the adsorbed water below 50% RH was not. Figure 8 shows the effect of humidity on the percent Journal of Pharmaceutical Sciences I 603 Vol. 82, No. 6, June 1993

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References and Notes

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state) and above the CRH (solution state). Carstensen et al.16 reported that the chemical stability of thiamine HC1 in microcrystalline cellulose tablets depended on the moisture content in the tablet and was minimum at -5% moisture. They stated that water content (-5%) of the tablets corresponded to the value required for the formation of a monolayer of water molecules, which was in the active degradation state. In our study, the water content of ranitidine HCl bulk powder was -0.1% at 60%RH, indicating that the surface was covered by multilayers (10-50 layers) of water. It appeared that the drug stability in solution (Scheme I) is related to the drug concentration because the initial pH of the solution depended on the concentration. On the other hand, because the drug concentration of the sample powders above 70% RH decreased with increasing RH (Figure 6),the percent degradation of the bulk powder decreased with increasing RH level (Figure 8).

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1 0 0 120 1 4 0

Absolute humidity, g-H O/m3 Flgun, &The relationship between percent degradation of ranitidine HCI bulk powder alter 288 h of storage and (A) RH and (B) absolute humidity at various temperatures. Key: (0)45 "C; (A)55 "C; (0) 65 "C.

degradation of ranitidine HC1bulk powder after 288 h (PD,,,) of storage at various temperatures. The maximum peaks of the plots of percent degradation versus RH overlapped at 60-70% RH for all temperatures, but the peaks of plots against absolute humidity did not overlap, indicating that the drug stability for the degradation differed among humidity regions below and above the CRH. The drug did not degrade in the solid state below 50% RH, but the percent degradation was maximum at 60-70% RH, being smaller above 70% RH than at 60-70% RH at all temperatures. Yoshioka et al.10 reported that the degradation profile of meclofenoxate HC1 bulk powder differed between humidity regions below (solid

604I Jocmal of Pharmaceutical Sciences Vol. 82, No. 6, June 1993

1. Zografi, G.Drug Dev. Ind. Pharm. 1988,14,1905-1926. 2. Yoshioka, S.Pharm. Tech. Japan 1990,6,891-904. 3. Carstensen, J. T.; Attarchi, F.; Hou, X. J. Pharm. Sci. 1985,74, 741-745. 4. Carstensen, J. T.; Attarchi, F. J. Pharm. Sci. 1988,77,314-317. 5. Carstensen, J. T.; Attarchi, F.; Hou, X . J. Pharm. Sci. 1988,77, 318-321. 6. Yoshioka, S.;Uchiyama, M. J. Pharm. Sci. 1986,75,92-96. 7. Aruga, M.; Awazu, S.; Hanano, M. Chem. Pharm. Bull. 1978,26, 2081-2091. 8. Genton, D.;Kesselring, U. W. J. Pharm. Sci. 1977,66,676-680. 9. Yamamoto, T. Yakuzaigaku 1963.23, 197-199. 10. Yoshioka, S.;Shibazaki; T.; Ejima, A. Chem. Pharm. Bull. 1982, 30,3734-3741. 11. Itoh, Y.; Shiraishi, N.; Muzuno, K.; Itoi, K.; Sasai, S. Zyaku Journal 1986,22,75-79. 12. Uzunarslan. K.: Akbuea. J. Phnrmazie 1991.46.273-275. 13. Geraldes, C: F. G. C.;&l, V. M. S.; Teixeira; M: H. S. F.; Feixeira, F. Mag. Reson. Chem. 1987,25,203-207. 14. Okiishi, T.; Shimizu, M.; Hashimoto, N.; Iguchi, R.; Kumon, S. Technical Information about the Stability of Ranitidine Hydrochloride, Shin-Nippon Jitsugyou. 15. Interview Form of Zantac tablet, Glaxo Sankyo, Company, Tokyo, Japan. 16. Carkensen, J. T.; Osadca, M.; Rubin, S. H. J. Pharm. Sci. 1969, 58,549353.

Acknowledgments The authors express their gratitude to Dr. Okiko Miyata for her advice on the degradation mechanism, Dr. Kayoko Saiki for her measurement of SIMS,and Mrs. Asako Ikeda for her assistance. The authors are also grateful to Glaxo Japan Company Ltd. for their generous gift of ranitidine HC1 bulk powder.