Arch. Pharm. Res. DOI 10.1007/s12272-014-0471-9

RESEARCH ARTICLE

Modulation of microenvironmental pH and utilization of alkalizers in crystalline solid dispersion for enhanced solubility and stability of clarithromicin Jun-Bom Park • Young-Joon Park Chin-Yang Kang • Beom-Jin Lee

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Received: 19 June 2014 / Accepted: 19 August 2014 Ó The Pharmaceutical Society of Korea 2014

Abstract Clarithromycin (CAM) is known to be poorly water-soluble and acid-labile drug. Various alkalizers such as MgO, Na2CO3, Na2HPO4 and NaHCO3 were utilized to modulate the microenvironmental pH (pHM) and to improve the low stability and solubility of CAM in a crystalline-solid dispersion system (CSD). Polyvinylpyrrolidone (PVP K-30) and hydroxypropylmethylcellulose (HPMC) 4000-based CSDs containing alkalizers were prepared by cosolvent precipitation followed by evaporation process. The dried-CSDs mixed with microcrystalline cellulose, 2 % croscarmellose sodium, and 1 % magnesium stearate was then directly compressed into tablet. A dissolution test was carried out in 900 mL of pH 5.0 buffer solutions at 37 °C with a 50 rpm paddle speed. pHM, surface morphology, and structural behaviors were investigated. The dissolution rates of CAM in CSD containing alkalizers were improved. The drug in CSD remained crystalline as observed by differential scanning calorimetry and powder X-ray diffraction. Scanning electron microscopy revealed nearly identical images regardless of the sorts and amounts of carriers. PVP-based CSD tablet without alkalizer showed greater drug release, while HPMC-based CSD tablet without alkalizer retarded drug release due to its greater swelling capability. However, when the alkalizers were added in CSD

J.-B. Park Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi, University, MS 38655, USA Y.-J. Park  B.-J. Lee (&) Bioavailability Control Laboratory, College of Pharmacy, Ajou University, Suwon 443-749, Korea e-mail: [email protected] C.-Y. Kang College of Pharmacy, Sahm Yook University, Seoul, Korea

tablet, the drug release was sharply increased. NaHCO3 induced the most rapid drug release while MgO retarded drug dissolution. Alkalizers in CSD also could maintain the pHM of the tablet above pH 5 under acidic conditions. The use of pH modifiers in CSDs could provide a useful method to improve the dissolution rate and stability of CAM via modulation of pHM without changing drug crystallinity. Keywords Crystalline-solid dispersion  Poorly watersoluble drug  Acid-labile drug  Alkalizer  Mmicoenvironmental pH

Introduction First discovered by Warren and Marshall in 1982 (2005 Nobel laureate), Helicobacter pylori was confirmed as a pathogenic agent at the end of the 1980s. The prevalence of this bacterium in the world is still high and the eradication rate has not reached the expected 90 % according to the WHO. Combined therapies (one or two antibiotics combined with a proton pump inhibitor) have proven effective in clinical application. However, other reports and clinical trials indicate that these therapies cannot completely eradicate H. pylori (Kawakami et al. 2001; Umamaheshwari et al. 2003). One of the major reasons for incomplete eradication may be the degradation of antimicrobial agents such as CAM and amoxicillin by gastric acid (Lin et al. 2002). CAM is a macrolide, orally absorbed, broad spectrum antibiotic. It is widely used in standard eradication treatment of gastric H. pylori infection. CAM has highest rate of eradication of H. pylori in mono-therapy in vivo. However, CAM is also unstable and rapidly degrades in the low pH of the gastric acid (Chun et al. 2005) and is also known to be poorly water-soluble in aqueous solution (Turner et al. 2005).

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Recently, solid dispersion systems have attracted increasing attention, and their promising results have demonstrated increased bioavailability of poorly water-soluble drugs (Onoue et al. 2009; Lee et al. 2013; Kim et al. 2014), in which the drug is dispersed in solid water-soluble matrices either molecularly or as fine crystalline particles (Chiou and Riegelman 1971). Several efforts have been made to design highly bioavailable dosage forms by modification of the crystalline form (Tran et al. 2010b; Ha et al. 2011; Tran et al. 2011c). Considering the poor solubility of CAM in the solution state (Yonemochi et al. 1999), the solid dispersion (SD) approach might be a viable formulation option for CAM. The crystalline solid dispersion (CSD) among the SD system was highly recommended so that in general, amorphous substances are chemically and/or physically less stable than crystalline substances (Kawabata et al. 2010). In our previous study, we described the modulation of the microenvironmental pH (pHM) using alkalizers in hydrophilic polyethylene glycol 6000 solid dispersion (SD) in order to enhance its dissolution (Tran et al. 2010a, 2011b, d). The pHM can be defined as the pH of the saturated solution in the immediate vicinity of the drug particles and has been used to modify the dissolution of ionizable drugs from pharmaceutical formulations in a predictable manner. The roles of pH modifiers could be varied by the types and preparation method of solid dispersions (Tran et al. 2010b, 2011a). To overcome the low solubility and stability of CAM under acidic conditions, we proposed a CSD system containing alkalizers. The aim of this study was to investigate the effect of incorporating alkalizers into HPMC 4000- and PVP K-30-based CSDs on the dissolution rate and stability of CAM. The alkalizers MgO, Na2CO3, Na2HPO4 and NaHCO3 were selected on the basis of their strong alkalinity. HPMC 4000 and PVP K30 were selected as sustained or immediate carrier, respectively in the manufacture of CSD using the cosolvent method. The modulation of pHM and the drug crystallinity were extensively characterized. The structural behavior and molecular interactions of the CSD containing alkalizers were also examined by instrumental characterization using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR). The gradient changes of pHM when CAM was in tablet form were also investigated as a function of time at different fractional distances of tablet length to elucidate the pH-modifying mechanism.

Materials and methods Materials CAM was provided by Sandoz (Barcelona, Spain). HPMC 4000 and PVP were provided by Shin-Etsu (Tokyo, Japan)

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and BASF (Ludwigshafen, Germany), respectively. Magnesium oxide (MgO) was purchased from Junsei Chemical (Tokyo, Japan), sodium bicarbonate (NaHCO3), sodium carbonate (Na2CO3) from Sigma-Aldrich (St. Louis, USA) and disodium hydrogen phosphate (Na2HPO4) from Showa Chemical (Tokyo, Japan). The solvents used were high performance liquid chromatography (HPLC) grade. All other chemicals were of analytical grade and were used without further purification. HPLC analysis for determination of drug A Waters Alliance 2695 HPLC system (Milford, USA) was used to analyze CAM, together with a 996 Photodiode Array (PDA) detector and EmpowerÒ. An analytical column (150 9 4.6 mm, Luna 5-lm C18) was used. For drug analysis, the UV detector was set at a wavelength of 210 nm. A mixture of Monobasic Potassium Phosphate 0.067 M and methanol (35:65) was used as the mobile phase. The entire solution was filtered using a 0.45-lm membrane filter (Millipore Corp., Bedford) and degassed before running the HPLC analysis. The system was run at a 1 ml min-1 flow rate and the running time was 12 min. The injection volume was 20 ll. Stability test of CAM 100 mg of CAM was placed in 100 ml of pH 1.2, 2.0, 3.0 or 4.0 buffer solutions in a volumetric flask. The flasks were then placed in a thermostatic vibrator and vibrated at 50 rpm at 37 ± 0.5 °C for 10, 20, 30, 45, 60, 90, 120, 180, 240 or 360 min. Samples were withdrawn at different time intervals and neutralized with sodium hydroxide solution (0.05 M) to adjust the pH of the sample to approximately 5.0 in order to prevent further degradation of the drug (Rajinikanth and Mishra 2008). The samples were taken out at different time intervals, filtered through a 0.45-lm syringe filter, and then analyzed for CAM content by the RP-HPLC method. The samples were assessed in triplicate. Preparation of CSD and its tablet The binary CSD was prepared by the co-solvent method. CAM (250 mg) was dissolved in acetone under stirring. HPMC 4000 or PVP (250 mg) were also dissolved in 80 % ethanol under stirring. Then, both mixtures were vigorously mixed using a mechanical stirrer. The samples were evaporated and dried in an oven at 50 °C. To obtain ternary CSD, 25 mg of pH-modifier (MgO, Na2CO3, Na2HPO4 and NaHCO3) per tablet was added to binary solution and stirred to form a uniform mixture. The dried CSD sample was then passed through a 60-mesh sieve to prepare tablets. The resultant mixture

Modulation of microenvironmental pH and utilization of alkalizers

(525 mg) was blended with 155 mg microcrystalline cellulose (180 mg in the case of binary CSD), then with 13 mg croscarmellose sodium, and finally with 5 mg magnesium stearate. The homogeneous mixture was directly compressed into 700-mg tablets equivalent to 250 mg CAM by round punches and dies with a 12-mm diameter. The hardness was controlled at 80 ± 10 N. Physicochemical properties of CSD Thermal analysis (DSC) The thermograms of pure CAM, HPMC, PVP, binary CSD (drug and HPMC or PVP), and all ternary CSDs containing 4 sorts of alkalizers were obtained by scanning from 30 to 350 °C at a scan rate of 5 °C min-1 using a differential scanning calorimeter (TA Instruments, Model 2910, USA). The samples (0.4–0.5 mg) were weighed in a standard open aluminum pan, with an empty pan used as a reference. Nitrogen was used as a purge gas. Calibration of temperature and heat flow was performed with indium. Powder X-ray diffraction (PXRD) A D5005 diffractometer (Bruker, Germany) with Cu-K radiation at a voltage of 40 kV, 50 mA was used to investigate PXRD patterns of all samples, including pure CAM, HPMC, PVP, and binary or ternary CSD containing alkalizers. The samples were scanned in increments of 0.02° from 5° to 60° (diffraction angle 2h) at 1 s/step, using a zero background sample holder.

membrane filter. The concentrations of CAM were then analyzed by HPLC. Micro-environmental pH (pHM) evaluation The enzyme-free simulated gastric fluid (pH 1.2) was used to investigate the change of pHM on CAM-CSD tablets (Tran et al. 2008). The non-disintegrated tablet was removed from the acidic dissolution media at 0, 30, 60 and 120 min and frozen immediately at -40 °C in a deep freezer for 30 min. The surface and inner pHM of the tablet were then assessed potentiometrically using a surface pH electrode (Metoxy pH Meter HM-17MX, DKK-TOA Corp., Japan). The tablets were cut into three slices. Depending on the fractional dimension of tablet length, the tablet surface and inner regions were determined and designated as d/d0 = 0, 1/2 or 1, respectively. The d0 was the distance from the edge to the center. We assumed that the pH gradients from the center of the tablet to both margins were similar. d/d0 = 1 represents the center, whereas d/d0 = 0 indicates the edge (surface) of the tablet. The pHM was plotted as a function of time at different fractional distances (d/d0). Water uptake of matrices The effect of water uptake on the matrix tablets containing CAM was analyzed by gravimetric evaluation (Ching et al. 2008; Jannin et al. 2006; Martin et al. 2002). The swelling ratio (SR) was calculated according to Eq. (1): SR ¼

Fourier transform infrared spectroscopy (FT-IR) A FT-IR spectrophotometer (Model Excaliber Series UMA-500, Bio-Rad, USA) was used. The wavelength was scanned from 500 to 4,000 cm-1 with a resolution of 2 cm-1. KBr pellets were prepared by gently mixing 1 mg of the sample with 200 mg KBr.

Wwet W0

ð1Þ

W0 is the weight of the initial matrix tablet and Wwet is the weight of the hydrated matrix tablet at a given time (t). The samples were kept at room temperature for ten minutes on paper wipes before measuring the tablet weight.

Results and discussion Characterization of CSD tablets Drug stability of CAM under acidic conditions Dissolution studies Dissolution was performed in enzyme-free pH 5.0 sodium acetate buffer solution according to USP 34- NF 29 ‘‘Clarithromycin Tablets’’. The 700-mg tablet containing HPMC-based CSD or PVP-based CSD equivalent to 250 mg CAM was exposed to 900 mL of fluid at 37 °C using the USP dissolution method II at a rotation speed of 50 rpm for 2 h (DST-810 dissolution tester; Labfine, Seoul, Korea). The samples were withdrawn at 15, 30, 45, and 60 min. The samples were filtered through a 0.45-lm

The stability and the time to reach the 50 % degradation of CAM under various acidic conditions were determined and shown in Fig. 1. The results indicate that the stability of CAM was significantly enhanced as pH increased. At pH 1.2, over 60 % of CAM degraded within 10 min and no CAM was detected at 45 min. However, the CAM was almost 80 % intact in pH 4.0 medium until 60 min. The degradation of antibiotics in acidic medium is quite an appreciable portion. Thus, most of the present studies of CAM for eradication of H. pylori are focused on

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prolonging the gastric retention time and preventing the degradation against the gastric juice. CAM was also reported to be unstable in media with low pH (Erah et al. 1997; Nakagawa et al. 1992). The stability test was not carried out with solutions above pH 5.0. Because the dissolution test was performed in pH 5.0 sodium acetate buffer solution according to USP 34-NF 29 ‘‘Clarithromycin Tablets’’, we can assume that the CAM was stable over pH 5.0 solutions. Physicochemical properties of CAM-loaded CSD Generally, the thermal behaviors of drug formulations are also important in pharmaceutical technologies, since the melting point, re-crystallization, decomposition, or change in heat capacity could help to ascertain the physicochemical status of the entrapped drug inside the excipient (Kawabata et al. 2010). We analyzed the crystalline structure of pure drug, HPMC, PVP, HPMC-based CSD and PVPbased CSD with and without alkalizers using DSC (Fig. 2) and PXRD (Fig. 3). According to DSC results, the pure drug had a distinct melting peak at 220 °C, whereas HPMC, PVP and four sorts of alkalizers had amorphous structures (data not shown). However, HPMC-based CSD and PVP-based CSD with or without alkalizers had a clear melting point around 220 °C, indicating that the drug still had a crystalline structure. All kinds of CSD showed small transitions of temperature and reduced peak intensity of the distinct drug melting point, implying their crystalline structure and suggesting that the transition of the thermal behavior in the CSD formulation was due to the co-existence of the excipients (Kawabata et al. 2010). To characterize the molecular properties of the CSD formulation in more detail, crystalline behaviors were also

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clarified by PXRD (Fig. 3). CAM is naturally crystalline whereas HPMC and PVP are amorphous. All kinds of HPMC-based and PVP-based CSD maintained the crystallinity and exhibited PXRD patterns similar to CAM. These results suggest that polymorphic transformation or hydration might not occur during the CSD formulation, drying and milling process, supporting the results from DSC analyses. We then measured the FT-IR spectra of pure drug, HPMC-based CSD with or without alkalizers (Fig. 4a) and PVP-based CSD with or without alkalizers (Fig. 4b). CAM has three noticeable functional peaks: 1,730, 1,690 cm-1 for the C=O bond and 1,450 cm-1 for the C–C bond. After CSD process with or without alkalizers, three noticeable peaks were still observed in the FT-IR spectra and showed the same shape and intensity. Therefore, there was no molecular interaction between CAM and the alkalizers or carriers such HPMC and PVP. The morphology of the CSD was examined by scanning electron microscopy. The nano-sized or micro-sized CSDs containing CAM were rod-shaped with adsorbed smaller particles (Fig. 5). The HPMC-based or PVP-based CSD with or without alkalizers did not cause a significant change in morphology compare with pure drug. Basically, a solid dispersion can be defined as a distribution of active ingredients in molecular, amorphous, and/or microcrystalline forms surrounded by inert carriers (Chiou and Riegelman 1971). Herein, the newly developed CAM formulation in the present study is identified as a CSD of CAM. Drug release and swelling study The dissolution profiles of CAM in CSD tablets in pH 5.0 buffer solution are shown in Fig. 6. To clarify the

Modulation of microenvironmental pH and utilization of alkalizers

Fig. 2 DSC thermograms of CSD with or without alkalizer; a HPMC-based and b PVP-based

Fig. 3 PXRD of CSD with or without alkalizer; a HPMC-based and b PVP-based

Fig. 4 FT-IR spectra of CSD with or without alkalizer; a HPMC-based and b PVP-based

dissolution behavior and effect of carriers and alkalizers, dissolution tests on HPMC- or PVP-based CSD with or without alkalizers were carried out for up to 60 min. The

PVP-based CSD tablets without alkalizers released CAM faster than HPMC-based CSD tablets. The CSDs tablets containing alkalizers had faster dissolution rates than pure

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J.-B. Park et al. Fig. 5 SEM images of HPMCbased CSD with a MgO, b Na2CO3, c Na2HPO4 and d NaHCO3; PVP-based CSD with e MgO, f Na2CO3, g Na2HPO4 and h NaHCO3; i and j CAM raw material (different magnification)

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CSD tablets. NaHCO3, Na2CO3 and Na2HPO4 caused the greatest enhancement of drug release rate. In contrast, HPMC-based and PVP-based CSD tablets containing MgO had no significant effect on release rate compared with CSD tablets without alkalizer. It was evident that the addition of alkalizers other than MgO to HPMC- and PVPbased CSD tablets resulted in the best enhancement of the CAM dissolution rate. To understand the detailed roles of alkalizers in the CSD tablets, a swelling study was carried out in dissolution medium. The results of the swelling study are depicted in Fig. 7. When the carrier such as HPMC and PVP on the surface of the matrix is hydrated during dissolution, it generates an outer viscous gel layer. This phase then leads to matrix bulk hydration, swelling and erosion. The phenomena that govern the dissolution rate are the rate of matrix swelling, drug diffusion through the gel layer, and matrix erosion (Colombo et al. 2000; Conti et al. 2007; Wan et al. 1993). The HPMC-based CSD tablet had a greater swelling ratio than the PVP-based tablet and its weight increased by up to 250 % in 30 min, while the PVP-based CSD tablet had a decreased swelling ratio whether it contained alkalizers or not. The results of the swelling ratio from HPMC-based CSD tablets could be arranged in order of NaHCO3 [ Na2CO3 [ Na2HPO4 [ MgO[without alkalizer, while the PVP-based CSD tablet decreased the swelling ratio during 120 min. PVP-based CSD tablets could be arranged in order of without alkalizer[MgO [ NaHCO3 [ Na2CO3 [ Na2HPO4, but there was no significant difference among alkalizers. Considering both the dissolution rate and swelling studies, the release of CAM from HPMC-based CSD tablets was governed by swelling properties. The CAM was released quickly given the greater and faster swelling ratio of HPMC-based CSD tablets. NaHCO3, Na2CO3 and Na2HPO4 have water-soluble characteristics. These three

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kinds of alkalizers seemed to induce water penetration in the HPMC-based CSD tablet; consequently, the HPMCbased CSD tablet began to swell and disentangle (Tu and

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Fig. 8 pHM of CSD tablet with or without alkalizers at pH 1.2 dissolution media. HPMC-based a d/d0 = 0 (surface), b d/d0 = 1/2 and c d/d0 = 1 (center of tablet); PVP-based d d/d0 = 0 (surface), e d/d0 = 1/2 and f d/d0 = 1 (center of tablet)

Ouano 1977). While MgO is not a soluble agent in water, it has no significant effect on the dissolution rate compared to that of the HPMC-based CSD tablet without alkalizer. In contrast, the release of CAM from PVP-based CSD tablets is governed by erosion properties. The CAM is released quickly from the more and faster erodible PVP-based CSD tablet. In the same manner, water-soluble alkalizers could induce water penetration, a phenomenon that could cause

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more erosion of the PVP-based tablet, and MgO has a negative effect on erosion and drug dissolution rate. Modulation of micro-environmental pH for stability of CAM CAM must be stored above pH 5 unless the CAM will be quickly degraded (Erah et al. 1997). When the tablet

Modulation of microenvironmental pH and utilization of alkalizers

containing CAM faces acidic conditions in dissolution medium or gastric fluids, which will easily penetrate into the tablet, the pHM falls below pH 5 at which it is possible that degradation of the CAM will occur before it leaves out from the tablet. Thus, the pharmaceutical dosage form containing CAM must sustain the pHM above pH 5. In our previous study, alkalizers or acidifiers were used to modify the pHM of a solid dosage form, leading to a change of drug dissolution (Tran et al. 2008). In this study, alkalizers were used to maintain the pHM above pH 5 on the CAM-loaded CSD tablet. Figure 8 shows the change of pHM as a function of time in simulated gastric fluids. For efficient pHM modulation, pH modifiers must stay inside the dosage forms and maintain the pHM (Kranz and Wagner 2006; Siepe et al. 2006). As the acidic dissolution fluid penetrates into the tablet, alkalizers leach out so that surface and inner pHM of the tablet can vary. The amount of alkalizers on the surface of the tablets can continuously decrease during the dissolution test (Tran et al. 2009). Thus, we also checked both pHM on the surface and in the inner core of the tablets. The pHM measurement is more reasonable than the solution pH since alkalizers can provide a non-acidic microenvironment around the drug particles. The bottom line is that decreasing the pHM could increase the degradation of CAM content within the tablet during a dissolution test of an acid-labile drug like CAM. Figure 8a–c show that alkalizers incorporated in ternary HPMC-based CSD produced a more basic pHM in the case of d/d0 = 1/2 and 1 than binary HPMC-based CSD without alkalizers. In the case of d/d0 = 1 (the center of tablet), the pHM decreased to below pH 5 after 60 min while the pHM of CSD with alkalizers was maintained above pH 6. If the alkalizers were not added to the tablet, the CAM would be degraded by acidic media after 60 min, before leaving itself from the tablet. The pHM of d/d0 = 1/2 was similar in the center of the tablet. The HPMC-based CSD tablet seems to need the alkalizers to prevent the degradation of CAM. Figure 8d–f also reveal the need for alkalizers in PVPbased CSD tablet. Comparing HPMC-based and PVPbased CSD tablets, the pHM of d/d0 = 1/2 and 1 showed similar patterns. We conclude that the alkalizers are needed and more efficient for modulating pHM of the CSD tablet according to whether the tablet has swelling properties (HPMC based) or erosion force (PVP-based).

Conclusions In the present study, HPMC- and PVP-based CSD and their tablets were prepared in order to improve the dissolution rate and stability of CAM under acidic conditions via

modulation of pHM without changing drug crystallinity. The drug dissolution rate in binary HPMC and PVP-based CSD tablet without alkalizers was not satisfactory regardless of the structural crystallinity. Alkalizers in the CSD tablet enhanced the dissolution rate of drug and maintained the pHM above the required pH 5. These results indicate that tablets of HPMC- or PVP-based CSD with alkalizers could be viewed as a stable delivery system for CAM for the treatment of peptic ulcer disease caused by H. pylori. Acknowledgments This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation funded by the Ministry of Science, ICT & Future Planning (2013M3A9B5075841) and by a Grant from the Korean Health Technology R&D Project (A092018), Ministry of Health and Welfare, Republic of Korea. We would like to thank KBSI for the use of SEM, PXRD, DSC and FTIR.

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