Polymorphic Transformation of Antibiotic Clarithromycin Under Acidic Condition

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Polymorphic Transformation of Antibiotic Clarithromycin Under Acidic Condition SHUJI NOGUCHI,1 KEI TAKIYAMA,1 SADAHIRO FUJIKI,1 YASUNORI IWAO,1 KEIKO MIURA,2 SHIGERU ITAI1 1 2

School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan Japan Synchrotron Radiation Research Institute, Sayo-gun, Hyogo 679-5198, Japan

Received 29 July 2013; revised 16 October 2013; accepted 3 December 2013 Published online 20 December 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23825 ABSTRACT: Clarithromycin (CAM) is a 14-membered semisynthetic macrolide antibiotic used to treat the infection of various bacteria including Helicobacter pylori. The polymorphic transformation of CAM form II crystals under acidic conditions is, however, still unclear, and was investigated using X-ray powder diffraction method. Gel of CAM, which was immediately formed by mixing form II crystals with the hydrochloric acid solution, transformed at first to unstable form A crystals and then to form B crystals. Both forms A and B crystals are hydrochloride salts. Analyses using Hancock–Sharp equation revealed that the mechanism of form B formation was three-dimensional growth of nuclei. The rate constant of the transformation indicated that the times for 95% of form A transforming to form B at 37◦ C are 0.69, 1.90, and 3.79 h at pH 1.5, 2.5, and 3.4, respectively. These suggest that the transformation from form II to form B via gel and form A could occur on the surface of form II formulation of prolonged gastric residence time, in the case that the pH in stomach stays C 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:580–586, 2014 low.  Keywords: clarithromycin; polymorphism; transformation; X-ray powder diffractometry; Dissolution rate; Stability

INTRODUCTION Clarithromycin (CAM; C38 H69 NO13 ; molecular weight 748.0; Fig. 1) is a 14-membered semisynthetic macrolide antibiotic used to treat the infection of various bacteria. CAM, using together with amoxicillin and proton pump inhibitor (PPI), is recommended as the first-line treatment choice to eradicate Helicobacter pylori,1 which is one of the etiologic factor of gastric carcinoma in human stomach.2 Eight crystal forms of CAM are reported so far: form 0 (ethanol solvate),3 form I,4 form II,5 form III (acetonitrile solvate),6 form IV (hydrate),7 form V,8 the hydrochloride salt,9 and the methanol solvate.10 Of these crystal forms, most stable form II is applied for clinical use in tablet11 and dry syrup formulations.12 At pH lower than 3.0, dissolved CAM is unstable and its cladinose ring is eliminated from 14-membered aglycone ring through an acidcatalyzed hydrolysis.13 The hydrolyzed CAM has no antibacterial activity,14 and this is the reason why CAM is used together with PPI for the eradication of H. pylori. In spite of this instability, CAM in tablet formulation is stable even in an acidic solution such as gastric fluid, and can be administered orally for the treatments of infectious disease caused by chlamydia, mycoplasma, and so on, without an enteric coating. Under the acidic solution lower than pH 1.5, CAM form II crystals rapidly transform to a transparent gel, and the gel formed on the tablet surface prevents the acidic solution from soaking into the tablets. This results in the protection of CAM in tablet from the inactivation through the hydrolysis, and in the retardation of the elution of CAM and disintegration of the tablets.15 It is unknown, however, whether the further polymorphic transformation of the gel occurs or not when the gel Abbreviations used: CAM, clarithromycin; PPI, proton pump inhibitor. Correspondence to: Shigeru Itai (Telephone: +81-54-246-5614; Fax: +81-54264-5615; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 103, 580–586 (2014)

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is exposed to the acidic solution for a longer time. Information on the polymorphic transformation of CAM under acidic condition is necessary to design new CAM formulations that stay prolonged time in stomach, as the fluctuation of pH in stomach would be possible in case of insufficient effects of PPI, not taking the PPI or changes in the physical condition of patients. The CAM formulation of prolonged gastric residence time is thought to be effective for the eradication of H. pylori, as the bacteria reside mainly in the gastric mucosa.16,17 In this study, we have investigated the polymorphic transformation of CAM form II under acidic conditions of hydrochloric acid solution using X-ray powder diffraction method, and found for the first time that the gel of CAM transform finally to the hydrochloride salt crystal via labile intermediate crystal. We report here the analyses of the transformation reaction mechanism and the rate constants using Hancock–Sharp equation,18,19 which describes the kinetics of isothermal solid-state reactions, and the dissolution behavior of the hydrochloride salt crystal.

METHODS Materials Bulk CAM form II powders, purity larger than 99%, were purchased from Shiono Chemical Company Ltd. (Tokyo, Japan). All reagents used were of the highest grade available from commercial sources. Preparation of Gel and form A Crystals Method for preparing the gel of CAM is described elsewhere.20 In short, 1.8 g of CAM form II powder was mixed with 25 mL of 0.1 M hydrochloric acid solution using a mortar and a pestle at room temperature. CAM form II powders transformed to viscous gel immediately after mixing is completed, as observed on the surface of form II tablets in hydrochloric acid solution.15 The gel transformed completely to fluent and glossy suspension

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RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Figure 1. Chemical structure of CAM.

of fine needle crystals, named form A, within 10 min. The form A crystal suspension was transferred to 50 mL centrifuge tube, and the crystals were collected by centrifugation at 7,200×g and 4◦ C for 5 min. Form A crystals thus collected were washed with 2 mL of ice-cold distilled water three to four times until pH of the wash water became 3.4 or higher. Form A crystals were stable at least 12 h when stored in wet state at 4◦ C. Form A was transformed to another crystal form, named form B, within 4 h by storing at 37◦ C under wet condition. X-ray Powder Diffraction Analysis Form A crystals were washed and suspended in hydrochloric acid solution of pH 1.5, 2.5, or 3.4. The suspended crystals were packed with the solution in Lindemann glass capillaries of 0.4 mm diameter by centrifugation at 180×g and 4◦ C for 1 min, and subjected to the X-ray powder diffraction studies. X-ray powder diffraction data were collected at SPring-8 BL19B2, which is equipped with Debye–Sherrer camera and a curved imaging plate detector.21,22 The wavelength was set at 0.9996 ˚ to reduce the background counts. The time intervals of the A diffraction data measurements for form A crystals in pH 1.5, 2.5, and 3.4 solutions were 10, 10, and 20 min, respectively, and the exposure time for each measurement was 5 min. During the data collection, the samples were kept at 37◦ C using N2 gas flow, and rotated at 1 rpm/min to reduce the possible preferential orientation. Powder diffraction data of form B, form II, and gel were collected at 25◦ C. Cell parameters of forms A and B were determined from X-ray powder diffraction data using N-TREOR0923 implemented in EXPO2013, the update version of EXPO2009.24 Rietveld refinement of form B crystal structure was performed using DASH25 and EXPO2013. The crystal structure of CAM hydrochloride salt8 was used as a starting model. Hydrogen atoms were generated at their theoretical positions using Jmol26 at the final refinement stage, and were refined as riding. Positional RMS difference of nonhydrogen atoms is a low value of ˚ 2 . Crystallographic data are summarized in Table 1, to0.090 A gether with Rietveld refinement statistics. Final Rietveld plot of form B is shown in Figure 2. DOI 10.1002/jps.23825

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Figure 2. Final Rietveld plot of form B. The experimental, calculated and difference diffraction profiles, and the background profile are drawn with blue, red, purple, and light green lines, respectively. Vertical navy bars at the bottom correspond to the positions of the Bragg peaks.

Kinetic Analysis of Transformation from Form A to Form B Using Hancock–Sharp Equation The ratio of form B crystal formed in the form A crystal suspension was estimated from the integrated observed intensities of the reflections (2 0 0) and (1 1 1) at 22 = 5.80◦ –6.10◦ . Hancock– Sharp Eq. (1) was fitted to the ratio to determine the mechanism of the formation of form B crystals: ln{− ln(1 − ")} = ln B + m ln t

(1)

 " = I(t) Imax

(2)

where I(t) is the summed observed intensities of (2 0 0) and (1 1 1) reflections of form B at time t, " is the fraction of form A transformed to form B, and m, B, and Imax were parameters determined by nonlinear least-square fitting. Rate constants for the formation of form B were calculated by nonlinear fitting of the data to Avrami–Erofeev equation for the three-dimensional growth of nuclei: − ln (1 − ") = (kt)3

(3)

All the calculations for nonlinear least-square fitting were performed using GraFit (Erithacus Software, Surrey, UK). Elemental Analysis of Form A Crystal Form A crystals washed with distilled water were dried under vacuum overnight. Elemental analyses for carbon, hydrogen, and nitrogen of the dried sample were carried out using CHN CORDER MT-5 (Yanako New Science Inc., Kyoto, Japan). Chloride ions in the dried sample were quantified using Mohr method.27 Dissolution Test of CAM Forms B and II by Static Disk Method Crystal powders of CAM form II or form B, 250 mg, were compressed into disks of 13 mm diameter using oil-press tableting machine (JASCO Corporation, Tokyo, Japan) at the tableting force of 10 kN. The CAM disks were fixed into the cylindrical holder. The surface area of the disk in contact with the dissolution medium is 1.33 cm2 . The holder was sunk into the bottom Noguchi et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:580–586, 2014

582 Table 1.

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Crystallographic Data and Rietveld Refinement Statistics

Crystal form

II

A

B

C38 H69 NO13

C38 H69 NO13 ·HCl·nH2 O

C38 H69 NO13 ·HCl·3.5 H2 O

P21 21 21

(C2)

P21 21 21

˚ ◦) Cell parameters (A,

a = 14.453 b = 34.689 c = 8.711

a = 14.476 b = 16.522 c = 19.218

Za 22 range (◦ ) Number of data points Number of parameters Number of restraints Rp , Rwp Goodness of fit

4

a = 27.515 b = 9.803 c = 23.372 " = 90.0 $ = 116.7 ( = 90.0 4b

Molecular formula Space group

a b

4 2.50 – 45.00 4251 255 96 0.030, 0.042 5.47

Number of CAM molecules in unit cell. This value is calculated on the assumption that space group is C2.

of the bottle containing 900 mL dissolution medium of 25 mM phosphate buffer pH 6.5, 5.0, or 3.0, according to Japanese Pharmacopoeia (JP) XVI. All these dissolution tests were performed under sink condition. The medium was stirred by paddle at 50 rpm according to the paddle method of JP XVI. Dissolved CAM concentrations were quantified by HPLC.15 Dissolution rates from the disks, K (mg L−1 min−1 ), were calculated from the slopes of the plots of dissolved CAM concentration against time. Saturated solubility, Cs (mg/L), of forms B and II were determined by shaking an excess of crystal powder sample with 50 mL of dissolution medium at 37◦ C for 3 days at pH 6.5 and 5.0 or for 1 h at pH 3.0, and analyzing the CAM concentration in the filtered supernatant. The solubility values of forms B and II at pH 3.0 were thought to be saturated ones because the CAM concentrations after 30-min shaking were identical to those after 1-h shaking. Apparent intrinsic dissolution rate, k (cm min−1 ), was calculated using following equation:  k = KV (SCs )

(4)

where V is the volume of the dissolution medium (900 mL) and S is the surface area that contact with a dissolution medium (1.33 cm2 ). Solubility and dissolution rates at pH lower than 3.0 were not examined because dissolved CAM is promptly hydrolyzed at the pH condition.

RESULTS AND DISCUSSION Figure 3 shows the X-ray powder diffraction patterns of CAM polymorphs appeared under acidic condition. By mixing with HCl solution, sharp diffraction peaks of form II (Fig. 3a) disappeared and form II transformed to amorphous gel that showed the diffraction pattern with diffuse scattering around 22 = 18◦ (Fig. 3b). The gel then transformed to form A crystal (Fig. 3c). In the diffraction pattern of the gel, sharp diffraction peaks of not form II but form A could be observed, indicating that form A immediately emerged after the gel was formed. Form A is a novel crystal form, as its X-ray powder pattern differs from those of CAM crystal forms reported so far. When form A crysNoguchi et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:580–586, 2014

Figure 3. X-ray powder diffraction patterns of CAM polymorphs.

tals were washed with distilled water and stored at 37◦ C under wet condition, its appearance changed from glossy one to white one within 4 h. X-ray powder diffraction patterns of the white crystals, named form B (Fig. 3d), was almost identical to that of CAM hydrochloride salt crystal,9 indicating that these are same crystal form. Form B was not transformed further even after the storage at 37◦ C for at least 3 days under wet condition. The vacuum-dried form A contained 1.24 mmol g−1 of CAM as calculated from the weight ratio of carbon determined by elemental analysis, and 1.12 mmol g−1 of chloride ion as determined by Mohr method (Table 2), demonstrating that molar ratio of chloride ion to CAM is nearly 1. Therefore, form A is thought to be another crystal form of chloride salt. Negatively charged chloride ion may be in ionic interaction with the positively charged dimethyl aminomethyl moiety of CAM in form A. Analysis of the observed X-ray powder diffraction pattern of form A with EXPO2009 suggested the cell parameters and the space group to be monoclinic C2 (Table 1). These cell parameters and space groups were well consistent with the observed X-ray powder diffraction pattern of form A: all the resolved Bragg peaks could be indexed using these cell parameters, and DOI 10.1002/jps.23825

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Table 2.

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Elemental Analysis of Vacuum-Dried form A Crystal

Weight Ratio of the Elements Carbon Hydrogen Nitrogen CAMa Cl Cl/CAM a b

56.3% 9.3% 1.8% 1.24mmolg−1 1.12 ± 0.08b mmolg−1 0.91 ± 0.07molmol−1

Mol. number of CAM in unit weight of dried form A crystal. Average and SD of five measurements.

no Bragg peak was found that was against the extinction rule of this space group (Miller indices h+k = even). Assuming that the space group is C2 and taking the molecular weight of CAM into account, asymmetric unit of form A (one quarter of unit cell, ˚ 3 ) is thought to contain one CAM molecule. Using the av1408 A erage volume per unit molecular weight of organic compound, 0.74 cm3 /g,28,29 volume of one CAM molecule is estimated to be ˚ 3 in asymmetric unit is ˚ 3 . This means that volume of 489 A 919 A not occupied by CAM molecule. This void volume may be occupied by a chloride ion and water molecules. Asymmetric unit of ˚ 3 , contains one CAM molecule, one chloride ion, form B, 1149 A and four water molecules, and the volume occupied by solvent ˚ 3 . Using these values, asymmetric as calculated above is 230 A unit of form A is estimated to contain one CAM molecule, one chloride ion, and at least 10 water molecules. The ratio of the volume occupied by solvents in form A is 34.7%. This value is very high for the crystal of low-molecular-weight organic compound and is comparable to those of macromolecular protein crystals that are usually fragile.29–31 Because of the high water content, intermolecular contacts between CAM molecules in form A crystal might be sparse and rearrangement of CAM molecules might be easy to proceed even in crystalline state. This could explain why form A is liable to transform to form B. The rate of transformation from form A to form B was complete within 4 h at pH 1.5–3.4 (Fig. 4). All the diffraction peaks observed during the transformation could be indexed using cell parameters of forms A and B. This indicates that no other intermediate crystal form is involved in this transformation. Time-course change of the fraction of form B transformed from form A showed clear sigmoidal patterns at pH 1.5, 2.5, and 3.4 (Fig. 5), suggesting that the mechanism of the transformation is three-dimensional growth (m = 3 in Eq. (1) or two-dimensional growth (m = 2) of nuclei. When Eq. (1) was fitted to the data of time-course change of form B fraction, the parameters m converged to 2.69, 3.05, and 3.29 for pH 1.5, 2.5, and 3.4, respectively. Therefore, the mechanism of form B formation was thought to be threedimensional growth of nuclei. Fitting the Eq. (3), which is equivalent to Eq. (1) of m = 3, to the data of time-course change of form B fraction revealed the rate constants, as listed in Table 3. The rate constants increase as pH decreases. As the Table 3.

Rate Constants for Transformation from Form A to Form B

pH

k (h−1 )a

1.5 2.5 3.4

2.10 ± 0.03 0.76 ± 0.02 0.38 ± 0.01 a

Standard errors are shown after the “±” sign.

DOI 10.1002/jps.23825

Figure 4. X-ray powder diffraction patterns during the transformation from form A to form B under acidic conditions. (a) pH 1.5, (b) pH 2.5, and (c) pH 3.4.

solvent content of form A is thought to be very high as described above, chloride ions might not be tightly fixed in the form A crystal and, moreover, might be freely exchanged with those in the bulk solution outside the crystal, as is usual in macromolecule crystal of high solvent content.32 The chloride ion in form A may be in equilibrium between ionically bonded state to the dimethyl aminomethyl moiety of CAM and freely diffusing state in the large solvent region in the crystal. Because the chloride ion in form B crystal structure is fixed by Noguchi et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:580–586, 2014

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Figure 5. pH dependence of the rate of form B formation. Solid lines are drawn using Eq. (3) fitted to the observed data at pH 1.5 (red circles), pH 2.5 (green squares), and pH 3.4 (blue triangles).

ionic bond with dimethyl aminomethyl moiety of CAM,9 the transformation from form A to form B would be rapid if the ratio of chloride ion bonded to the dimethyl aminomethyl moiety is high in form A crystal. The concentration of chloride ion in hydrochloric acid solution is higher as pH decreases, and the ratio of chloride ion bonded to the dimethyl aminomethyl moiety would be also higher at lower pH. This might explain the faster rate constants of the transformation at lower pH. On the basis of the rate constant of the transformation, the time for 95% of form A transforming to form B at 37◦ C is 0.69, 1.90, and 3.79 h at pH 1.5, 2.5, and 3.4, respectively. As it takes approximately 10 min for form II to transform to form A via gel, the transformation from form II to form B via gel and form A might occur in human stomach in the case that CAM form II formulation having gastric residence capability of half to 1 day is administered and the pH in stomach stays low. This suggests that elution from form B, as well as form A, should be taken into account when designing or administering the form II formulation of gastric residence capability. In the crystal structure of form B refined by Rietveld method, a hydrogen bond network is formed between CAM molecules directly and via water molecules and chloride ions (Fig. 6). Intermolecular hydrogen bond parallel to a-axis is formed between hydroxyl oxygen atoms of 14-membered aglycone ring (O17) and cladinose ring (O10) of CAM. This intermolecular hydrogen bond is commonly observed in the crystal structures of Table 4.

Form B

a b

form I,33 form 0,34 and form IV.35 Nearly parallel to the plane formed by a- and b-axes, two water-mediated hydrogen bonds are formed between hydroxyl oxygen atom (O13) of desosamine ring and hydroxyl oxygen atoms (O16 and O17). Along c-axis, hydroxyl oxygen atom (O10) of cladinose ring and nitrogen atom (N1) of desosamine ring is connected through an ion bond and hydrogen bond via chloride ion and water molecule. This threedimensional network of the intermolecular interactions would promote the growth of form B crystal in three-dimensional direction, as revealed by the analyses using Hancock–Sharp equation described above. Dissolution rates from disks of form B and form II crystals increase as pH decreases (Fig. 7 and Table 4). The rates of form B is much higher than those of form II, as is expected from the fact that weak basic CAM forms salt with strong acid of hydrochloric acid in form B crystal. This means that even if small amount of form B crystals are grown on the surface of CAM form II formulation in the stomach just after the administration, they would soon disappear through dissolution and the elution of CAM would be mainly from form II when pH in stomach raise to pH 5–6 owing to PPI that is usually administrated with CAM for the eradication of H. pylori. The dissolution rate of form A was not determined, because a disk of form A could not be prepared because of its liability to transform to form B

Dissolution Parameters of Forms II and B pH

Form II

Figure 6. Packing view of CAM form B crystal. The unit cell is drawn with thin gray lines. The carbon, nitrogen, oxygen, and chloride atoms are shown in green, blue, red, and gray, respectively. Hydrogen atoms are not drawn for clarity. Hydrogen bonds are drawn as black dotted lines. Ionic bonds between nitrogen and chloride atoms are drawn as orange dotted lines.

3.0 5.0 6.5 3.0 5.0 6.5

Dissolution Rate from Diska (mgL−1 min−1 ) 7.54 2.01 4.88 2.40 2.15 1.95

± ± ± ± ± ±

0.07 × 10−1 0.07 × 10−1 0.11 × 10−2 0.01 0.04 0.02

Solubilityb (mgL−1 ) 4.15 2.76 1.26 1.27 1.27 7.85

± ± ± ± ± ±

0.04 × 103 0.06 × 103 0.04 × 103 0.02 × 104 0.04 × 104 0.10 × 103

Apparent Intrinsic Dissolution Rate Constant (cmmin−1 ) 1.23 4.94 2.62 1.28 1.15 1.68

± ± ± ± ± ±

0.02 × 10−1 0.21 × 10−2 0.10 × 10−2 0.03 × 10−1 0.04 × 10−1 0.03 × 10−1

The dissolution rates and their estimated SDs are calculated by linear least-square method. Averages and SDs of three measurements.

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RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

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Figure 7. Dissolution profiles of CAM form B and form II by static disk method. Form B at pH 3.0 (red triangles), pH 5.0 (red diamonds), and pH 6.5 (red circles), and form II at pH 3.0 (blue triangles), pH 5.0 (blue diamonds), and pH 6.5 (blue circles).

and its high instability against drying. However, the dissolution rate of form A is supposed to be higher than that of form B, because form A is thermodynamically less stable than form B as evident from the fact that form A spontaneously transforms to form B. Therefore, increased release of CAM by form B would be enhanced when form A coexists. The high dissolution rates of forms B and A suggest that even though the release of CAM from form II formulation might be suppressed at first by the gel formation under acidic pH condition such as in stomach, the release would be subsequently enhanced by the formation of form B from the gel via form A.

CONCLUSIONS Under the acidic condition, most stable form II of CAM transforms first to gel, then to form A, and finally to form B. Form A, a novel hydrochloride salt crystal, is highly unstable and easily transformed to another hydrochloride salt of form B. The instability of form A might be explained by its high solvent content. Analyses using Hancock–Sharp equation revealed that the mechanism of form B formation is three-dimensional growth of nuclei. The mechanism is in well accordance with the crystal structure of form B, in which three-dimensional network of CAM is formed via hydrogen and ionic bonds. The rates of form B formation suggest that the transformation from form II to form B via gel and form A would occur within the order of hours even in stomach. As the dissolution rate of form B is faster than that of form II, the release of CAM from the form II formulation of prolonged gastric residence time might be temporary enhanced in the case that the gel of CAM is accumulated and form B is formed from the gel.

ACKNOWLEDGMENTS The synchrotron radiation experiments were performed at BL19B2 of SPring-8 with the approval of the Japan Synchrotron Radiation Research Institute (JASRI; Proposal No. 2012A1733 and 2012A1043). DOI 10.1002/jps.23825

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