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`RESEARCH ARTICLE
`
`h«p:〃mför¥»ahe^thcaf^K：om/^di
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`SSSN; 0363-9걍45 (print), 1520-5762 (electronic)
`
`Drug Dev !nd Pharm, Eady Online: 1-7
`© 2013 拓form교 어e기the교徒 USA, inc DOI: 10.3 !Ö9/Ö3639O와5.2013859154
`
`informa
`
`health《죠re
`
`Aluminum 쪊mtion and pr쎦opitation in glass vials: effect of pH and
`buffer speci쎦s
`
`Toru Ogawa\ Makoto Miyajima\ Naoki Wakiyama', and Katsuhide Terada-
`
`'Formusation Technology Research LaborGtones, Daiichi Sonkyo Co., Ltd., Hkotsuko, Konogawa, Japan and ^Foculty of PhorrnGceuticGl Sciences,
`Toho University, Funabashh Chiba, Japan
`
`Abstract
`拍organic extractabies from glass vials 1■nay cause 卩갰出de formation in the drug solution, !n this
`study, the ability of e旭tin이 Al bn from borosiHc겨蚀 glass vials, and tendencies of precipitation
`containing Al were investigated using various p너s of phosphate, ci廿겨Ee, acetate and histidine
`buffer Through heating, aH of the buffers showed that Si and Ai were eluted from glass vials in
`ratios almost the same as the composition of borosilicate giass, and the amounts of Al and Si
`from various buffer so心Hons at pH ' 1 were in the foHowing order: citrate > phosph갰te >aceA
`ate>histidine. !n addition, during storage after heating； the Al concentration at certain pHs of
`phosphate and acetate buffer solution decreased, s있ggeshng the formation of particles
`containing Al, In citrate buffer, Aä did not decrease in spiE샨 of th샨 high 샨恒tion 겨mo럈nt.
`Considering that the solubility profile of aluminum oxide and the A! eluting profile of
`borosilicate glass were different, it is speculated that Al ion may be forced to leach into
`the buffer s시이む〇门 according to Si elution on the surface of glass vials. When AS ions were
`져dded to the buffer solutions, phosphate； acetate and histidine buffer showed a decrease of
`Ää concentration d럈rirtg storage at a ne럈廿겨i range of pHs, indicating the formation of particles
`cont계mng AL In conclusion, it is suggested that phosphate buffer solution has higher
`possibility of forming parfi이es confining Al than other buffer sokftions.
`
`Keywords
`Acetate buffer, aiuminum； borosiiicate 이ass
`citrate b럈ff샨r, extractables, histidine buffer,
`phosphate buffer
`
`Hsstory
`Received 9 July 2013
`Revised 10 October 2013
`Accepted 21 October 2013
`Published online 22 November 고013
`
`introduction
`For in.|ectable drugs, p차rticukwly for liquid injectables, compo­
`nents of the Qru농s are regular!\- In contact with the surface of rhe
`packaging systems which should protect the drug against any
`contamination from the external environment during storage.
`Therefore, it is essential to evaluate the physieoeheraical
`compatibilit\- between the drug Rirmulation and the packaging
`components in order to select appropriate primary packaging
`systems 게üri寡g the course of formulation development of
`injectable drugs^"\
`Among the packa농mg materials that are compatihle with
`injectable drug solutions, glass containers, such as vials or
`ampoules, have been widely chosen and used. BorosiHc갔t己 glasses
`in partieular are known to have good chemical durability and are
`used commonly in the pharmaceutical industry as the primawy
`container^, However, these glass containers, even, when made
`from borosilicate glass, c갔n pro게u。。some undesirahle events that
`unavoidably occur from being in contact with drug solutions in
`long-term storage'^. Formation of particles in drug solutions is
`
`Address for correspondence: I. Ogawa, Formulation Technology
`Research Laboratories, Daiichi Sankyo Co,, Ltd., 1-12-1 Shinomiya,
`Hiwa槌uka, Kanagawa 254-0014, Japan. Tel: +-81-463-31 -640S. E-maii:
`ogawa.toru.ir@'daiic1iisankyo.cojp
`
`well-known 차wnoug drug manufacturers, as one of the events from
`incompatibility between a drug solution and glass com：갔ine匚
`Some researchers have reported that some elements in drug
`solutions are known to induce the degradation of glass surfaces,
`which coロー'이ates with p印ゴi시e formation, as the result of
`delamination on the d^’gr敏ie게 sürf갔cS. Brown et aL\ Bacon
`et 갔 1.8 and Ernsberger^ evaluated gl갔ss corrosion focusing on
`phosphate buffer, citrate buffer and EDTA, respectively. lacocca
`et aL’° also reported a correlation between glass eorrosion and
`Si〇2 elution, using glutaric acid.
`In addition to the delamination, in the case of storing
`glass vials coWamiHg drug solution, there is another mechanism
`to form particles during the storage; a precipitation due to
`chemical interaction between the drug solution 차nd extractahles
`from the glass v询s There are some researchers^ who
`reported the precipitation of the drug solution and there are 갔 180
`researchers"丄〉who discussed extractables from the glass;
`however, there is less comprehensive information on the effect
`of the interaction between the drug solution and the extractables.
`As we reported prfMoロ노。七 phosphate buffer solution in a
`borosilicate glass vial h갔s the ability to form particles due to
`interactions with the 시uminum (Al) that is elnted from the glass
`during storage, Silicon (Si) elution at the time the particies formed
`in phosphate buffer solution 啊‘a이 2-8 ppm and these values are
`thought to he lower than those from reports th갔t mention about
`glass cormsio建M'". These results suggest that the particles in
`
`CONFIDENTIAL
`
`ExelaCYSOOl 08732
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`EXELA 2017
`Nexus Pharmaceuticals v. Exela Pharma Sciences
`PGR2024-00016
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`1
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`

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`2 T. Ogawa et al.
`
`phosphate buffer solution can be formed under a situation where
`glass degradation hardly occurs on the surface of glass vials. The
`issue of Al-phosphate complexes leading to particle formation
`should therefore be brought to the attention of researchers
`working on drug formulation.
`Citrate buffer, acetate buffer, and histidine buffer ai*e also
`selected for injectable drug products, especially biological drugs,
`in order to maintain the pH of the drug solution within the
`appropriate range from the point of view of drug stability. The
`ability of these hufters to elute Al from glass vials and induce
`particle formation should be evaluated.
`In this study, we investigated the ability of the four aforemen-
`Ho寡e게 buffer solutions to elute Al from glass vials 게 the
`tendency to form Âbcontaining precipitates.
`
`Materials and methods
`Materials
`Dibasic sodium phosphate, monobasic sodiuni phosphate, sodium
`chloride, citric acid, sodium citrate and acetic acid were all
`이peci차Lgfade reagents purchased from Kanto Chemical (Tokyo,
`Japan) or Wak.o Pure Chemical Industries (Osaka, J차oan).
`L-Histidirie was of USP cownp己mliuE교 quality pürch갔%d from
`Research Organics Inc, (Cleveland, OH). For pH adjustment,
`1 molZL or 0.1 mol/L of aqueous sodium hydroxide or aqueous
`hydrochlorie 차cid were purchased from Kanto Chemical or Wako
`Pure Che21ic갔 1 Indu노Si¢洛, Both aluminum oxide powder (α type,
`p갔rti一ci己 size 35—50 卩m) 갔nd silieou dioxide (amorphous, particle
`size approximately 3--25 p.m) were purchased from Kanto
`只 Chemical, The other chemicals were all commercially 차v차ilabl%
`reagent-grade cheniic시s. All water used in this study was
`〇
`3
`üls유 p 山:e water supplied by an ultrapure water system
`(Mi나ipor巳 Billerica, MA).
`즘
`Borosilieate (Type J) tubing glass vials (colorless, 10 raL) were
`皖
`廿 obtained from Fuji Glass (Tokyo, Japan) without any special
`ェ treatment on the surface. The glass vials were manufactured from
`glass tubes supplied by Nippon Electric Glass (Smg갔, Japan).
`Plastic vials (Daikyo CZ resin, colorless, 1 〇 siiL) were obtained
`from Daikyo Seiko (Tokyo, Japan). l^or rubber ck龍we& S10-F6,
`D777-1 and RB2-40 closures were obtained from Daikyo Seiko.
`
`Suffer preparation
`Phospむ갔t己 buffer solutions were prepared from monobasic sodium
`phosphate or dibasic sodium phosphate and sodium hydroxide,
`citrate buffer solutions were prepared from citric acid and sodium
`hydroxide, acetate buffer solutions were prepared from aceSte
`and sodium hy게 10xide, and histidine buffer solutions were
`prepared from histidine or histidine chloride aR세 hydrochionc
`acid, respectiveh\ All of the buffer solutions contained 0.9%
`sodium chloride, whieh served a이 a tonicity agent.
`
`Preparing buffer solutions with abminum (ÂI) ions
`The given concentration of alurninuni (Al) ions was Dr己p갔re。by
`diluting an Al stai招ar게 solution for ICP lOOOrng/L (Kanto
`Chemical) with the buffer solution. To eliminate the amount of
`Al eluted from a glass vial, these solutions were stored in plastic
`vi싱 s.
`
`Drug Dev Ind Phaim. Early OMme: 1-7
`
`a 0.22 gm Mill ex GV Dnrapore membrane filter (Millipore), then
`lOmL was added to each vial in a clean bench, and the vial was
`immediately stoppered and capped. Each filled sample was stored
`갔t the given。〇n게itions or was he갔〔■己d to the given conditions in
`the steam sterilizer.
`
`Preparing suspensions containing powders in buffer
`solution
`Suspensions containing powder of 차Inmmunj一 oxide or silicon
`dioxide in the fonr kinds of hnffer 이oluüom一 were prepared by
`suspending approximately 10-30 mg of the powder with 5 niL of
`buffer solution (50 mM, pH 5 or 7) in a plastic tube (Becton
`Dickinson, Franklin Lakes, NJ), and the tube was stored at 25 °C
`for 2 d차ys or 6 months in a horizonSl position.
`
`Visual Inspection
`Each sample vial was inspected for insoluble particulate matter
`under a 5000 Lux light eoriditioik
`
`Particle counting
`To confirm the results of visual inspection and to measure sizes of
`particles, laser particle-counting instrument PC-2300 (Spectrex,
`CA) was used. Features of this 갔ppar滅ロ노 갔rf： 게escribe게 by lacoeca
`et aL’q Calibration was done u노nig polystyrene spheres (4—5 gm,
`ca. 960 partieles/mL). Prior to measurement, each vial exterior
`was wiped to remove surface cont차niinants and then the vial was
`gently 이wiH己d for 〜3 s.
`In this study, 갔H vials, which particles were observed by visual
`inspection (detectable size: more than 200 gm), were confirmed to
`be detected more than 5샤Oparficles/mL using this apparatus.
`
`Energy dispersive X-ray spectrometry (EDX) analysis
`EDX analysis w차s performed under the same procedure as
`reported previously using SEM-EDX (JSM-5600EV JED-2140,
`JEOE, Tokyo, Japan).
`
`港句y coupled plasma (ICP) analysis
`Al and Si concentrations were measured using inductively
`coupled plasma optical emission spectrometry (ICP-OES)
`(VISTA-PRO, Seiko Instruments, Chiba, J갔pan)。To avoid effects
`of precipitating p갔rüci己s or the powders on measurement, each
`sample solution was filtered through a 0.45 gm Millex HV
`Dnrapore membrane filter (Millipore) prior to the measurement.
`The filtrates were transferred into 차 polypropylene 15 mE plastic
`tube (Becton Dickinson). Standard solutions were prepared hy
`serial dilution of an ICP standard 1000 mgZL of multi-element IV
`(including Ag, Al, B, Ba, Bi, Ca, Cd, Co, Cr, Cu, Fe, Ga, In, K,
`Mg, Mn, Na, Ni, Pb, Sr, T1 and Zn) and an ICP standard 1000 m_g7
`E of Si (Merck, Darmstadt, Germany) with 0.9% sodium chloride
`solution. The nominal detection wavelength for analysis was
`396.152 nm for Al and 251.611 nm for Si, When measuring a
`sample just after conducting terminal 이terilizaiion, 1-lOn.iM of
`citrate buffer solution was added for the purpose of inhibition of
`precipitation of elements elute게 before analysis.
`
`FHUng and storage of the 阳m미建 sobtäon
`Rubber closures 갔nd plastic vials were washed with water and
`then autoclaved in a steam sterilizer (HV-25, Hirayama, Saitama,
`.Japan) at 121 °し for 30 min. Glass vials were washed with water
`차nd then heat sterilized in a clean oven (DRC633EÂ, Advantec,
`Tokyo, Japan) at 310 °C for 1 h. Sample solutions were filtered by
`
`Observation of partkies In various pH of phosphate
`buffer solutions in 웤|密ss viab during storage
`Table 1 shows the results of a visual inspection of the viais filled
`with pH 5-8 of phosphate buffer solution (10 and 5샤 mM) after
`storage at 40, 60 and 8() "C Under the 이forage condition at 40 °C
`for 3 months, particles were detected only in the sample of 50 rnKl
`
`CONFIDENTIAL
`
`ExelaCYSOOl 08733
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`2
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`

`

`DOI: 10,3109/03639045.2013.859154
`
`Aluminum elution and precipitation in glass vials 3
`
`Table 1. Results of visual Inspection of phosphate buffer solution (10 and
`50mM) in various pHs,
`
`I'able 2. Results of visual inspection of various buffer solutions (50 mM,
`pH 7).
`
`Solution
`Phosphate
`buffer
`〇야 mM)
`
`Phosphate
`buffer
`(50mM)
`
`Storage Vials detected particles/viais inspected
`pH 6
`Temperature:Pe310d
`pH 8
`pH 5
`pH 7
`3 months
`0/5
`0/5
`40 °C
`0/5
`0/5
`0/5
`1 month
`〇/5
`60-C
`0/5
`2/5
`0/5
`0/5
`2 months
`5/5
`0/5
`0/5
`3/5
`80て 2 weeks
`2/5
`0/5
`5/5
`1 month
`5/5
`5/5
`5/5
`3 months
`0/5
`0/5
`3/5
`0/5
`0/5
`2/5
`1 month
`3/5
`0/5
`0/5
`5/5
`2 months
`5/5
`0/5
`2 weeks
`0/5
`3/5
`3/5
`0/5
`5/5
`5/5
`I month
`5/5
`5/5
`
`40 °C
`60。C
`
`8。。C
`
`차t pH 7. At 60 °C for 2 months, particles were detected at pH 6
`and 7 for 50m^l 갔nd pH 7 for lOniM At 80 "C for 1 month, all
`samples contained p갔rtici己& and for 2 weeks, some partieles were
`detected at pH 6 and 7 for both 10 and 50 mM. All samples which
`were detected partieles visuaHy {ca 200--2000 卩m) were observed
`to contain, lots of subvisible (<50 |im) particles, since laser-
`p邳Ü사己 counting showed more than 500 partieles/mL. It is
`noteworth\? that average mean sizes of these particles were
`witbin a range of 5-10 gm (data not sbown) in comparison with
`the report which describes that average sizes of delaminated glass
`particles were 갔pproxim갔血y 20-25 卩m'% suggesting these par­
`ticles in this study are 게iffer£■泊t from delaminated glass particles.
`These results indicate that the tendency for the particle
`formation depends on the temperature and pH, Ag reported
`pfeviou아y'七 particles formed from a phosphate buffer in glass
`vials 갔ft己r storage are thought to be complexes of phosphate 갔nd
`Al which are eluted from the surface of glass vials. In that study,
`we used phosphate buffer solution at pH 7 and 16 mM as
`phosphate. Prom the results of this 이tody, it is thoughl that
`phosphate buffer solution at pH 6 and 7 has higher possibility of
`these particle formations than pH 5 갔寡d 8. Considering that
`5샤 n上M buffer solution at pH 6 formed particles at 60 °C for
`2 months but 10 mM did not, the higher eoncentration is thought
`to form more particles.
`
`Observation of partkies in phosphate, citrate, acetate am』
`histidine buffer solutions in glass vials dunn웤 storage
`Next, we performed another stability study using four kinds of
`buffer solutions; phosphate buffer, citrate buffer, acetate buffer
`and histidine buffer. The buffer solutions we used in this 이mdy
`were all 50 mM 갔寡d pH '7 and were stored at 40, 60 or 잉〇 °C tor up
`to 3 montbs. The results of visual inspection after storage are
`sbown in Table 2. Ju eitrate buffer and histidine buffer, no
`p印力시es were observed under these storage conditions. On the
`other h却kL acetate buffer formed particles in the samples stored
`at 60 and 응〇 "C as well 갔s phosphate buffer. The EDX analysis of
`the particles that were eollected from the acetate buffer (60 °C, 2
`이 showed Al and 〇, 차Hd hardly showed Si (data not
`shown). We confirmed the vials containing visually detectable
`size (ca. 200-500 gni) 갔iso had lots of subvisible particles
`detected by laser-particle eounting and these mean sizes were
`within a range of 5--10 gm (data not shown).
`I'hese results 이ugges£ that not only phosphate buffer hut also
`other buffer solutions are at risk to form particles containing AL
`Comparing the time to form these particles between in phosphate
`and acetate buffers at 60 °C, the panicles were formed in
`phosphate buffer earlier than in acetate buffer.
`
`Storage
`Temperature
`40 °C
`60 °C
`
`80 °C
`
`Vlais detected partlcles/vials inspected
`Acetate
`Ci ば ale
`Phosphate
`Histidine
`0/5
`0/5
`0/5
`0/5
`0/5
`0/5
`5/5
`0/5
`0/5
`5/5
`0/5
`2/5
`0/5
`5/5
`0/5
`5/5
`0/5
`5/5
`0/5
`5/5
`
`Period
`2 months
`I mentis
`2 months
`i month
`2 months
`
`Evaluation of eluting amount of Al 創爭』Si from glass
`vials by phosphate 혜i헤 other buffer solutions using heat
`treatment
`To confirm if the pH of phosphate buffer has an effect on the
`eluting terideney of Â1 and Si from a glass vial, we measured the
`Al and Si concentrations in phosphate buffer solution just after
`extraction at a high 龙niper차tuie. 디：he high 龙nipew차tuie eluting
`study was eondueted for 차 이hoH time to prevent the concentrations
`of extracted ions from r£：a사niig uriEic：갔 1 time that lead to undesired
`effects such as precipitation.
`Phosphate buffer solutions at various pHs (20 mM) were filled
`in 농1 차ss vials. Heat treatment (105 °し, 60 min) was performecL 차nd
`then each 이oluüom一 in the vial was transferred into a plastic tube,
`adding citrate buffer to inhibit preeipitation of Al complexes.
`The results of Al and Si eoncentration using the TCP method
`were shown in Figure L showdng that higher pH elutes both Al
`and Si higher in the 頒Hge of pH 4-11. It is noteworthy that the
`ratio of Si to Â1 of the sample just 갔世er hf；갔thよg was approxi­
`mately 10:1 in all of the tested samples having a detectable
`level of Â1 and Si (pH>6). The glass vial used in this stud\? was
`made of borosilicate glass tubing manufactured by Nippon
`Electric Glass. The amount of Si〇2 却触1 Al203 in the glass from
`Nippon Electric Glass is 70~75 and 5—1〇%% respectively, and this
`formulation means that the ratio of Si to Al as an atomic element
`is estimated to be approximately 6—1지 气 The ratio of approxi­
`mately 10 is quite similar to the ratio of the Si/Al concentration
`just after heating, suggesting that both Si 갔nd Â1 were elute게 from
`the glass vials in ratios similar to composition of the borosilicate
`glass, at any pH level.
`To compare eluting tendency of Al and Si from the glass
`祈갔i among the four kinds of buffer solution (phosphate, citrate,
`a睥t갔t己 and histidine), measurement of Al and Si concentration
`was conducted in addition to the 20 mM phosphate buffer
`solution. The four kinds of buffer solution (50 mM) were filled
`in glass vials and healed (105 ''C, 60 or 240 min), then Al 차nd
`Si were measured in the same manner as mentioned above. As
`well as pbosphate buffer solution, three other kinds of buffer
`solution showed that they elute A.1 and Si depending on their
`pH with the ratio of composition of tbe borosilicate glass
`(Figure 2).
`Bacon et al? r£：porfe게 that higher pH of citrate buffer eiufe게
`higher Si in glass vials after terminal sterilization (121 °C,
`60 min). Our results reveal thal not only Si but also Â.1 is 이uted
`from rhe glass vials depending on the pH,
`Figure 3 shows the results of Al 게 Si concentrations for 10 or
`50 mM of the four kinds of buffer solutions (pH 7) after heating at
`105 °C, 60rain. The order of eluting araounts of Al and Si from
`the fonr buffer solutions at pH 7 as f。］」。w缶；citrate > phos­
`phate > acetate > histidine. In addition, higher levels of Al and Si
`are eluted from 50 niKl citrate, phosphate and aa기:갔fe buffers
`T이ativE to 10 raM buffers indicating that elution frora glass vials
`depends on the eoncentration of the buffering agents,
`巍 f 瑟 费쎠 薑 竅
`
`CONFIDENTIAL
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`ExelaCYSOOl 08734
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`3
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`4 T. Ogawa et al.
`
`The tour kinds ot butter have ditterent pH-buttering capacity
`due to the differences of their pK旗 however, citrate buffer showed
`the highest Al and Si elution 차nimmtg 차?: all pHs in this study.
`These results suggest th갔t the eluting ability does not have a
`correlation with the buffering。갔pacify.
`From these results, it suggests that each buffer solution has its
`own eluting ability from 농1 차ss containers depending on tempera­
`ture, time and its concentration.
`
`Evaluation of concentration of Al during storage after
`heat treatment
`The tour kinds ot butter solution in the glass vials as descnbed in
`the previous section were stored at 5 °C for 5 months. After
`storage, the particles were ob이efved only in the samples in the
`r갔ng。of pH 6-9 of phosphate buffer, and in pH 6 and 7 of acetate
`buffer (data not shown). These p갔rücl己s were also dotE’c任/ by
`laser-particle counting. Each solution was filtered through a
`0.45 um filter, then the Al coneentration of the filtrate was
`measured (Figure 4). Comparing the Al concenrradons with the
`eoricentration before storage (i.e. jn노t after heating), 교ark갔ble
`decreases of Al concentration were observed in the range of
`pH 6-9 of phosphate buffer and in pH 7 of acetate buffer. On the
`other hand, in citrate buffer and histidine buffer, little change was
`observed before 갔nd after storage.
`It should be noted that the buffer。〇n게ifis洛 (pH 6, 7, 웅 and 9
`of phosphate buffer, and pH 6 and 7 of acetate 'buffer) in which the
`particles formed were identical to those in which Â1 concent/차ti。H
`decre갔sed. Previously, we reported that phosphate buffer solution
`
`.Al
`
`더
`〇
`
`9 s n IB더 o s j g d .10丄
`
`Figure I. Al i^opened ti'iangle) and Si (filled circle) cmicentrauons in
`phosphate buffer solutions (20 mM) in glass vials heated at 105 *"XJ for
`60 mm.
`
`Al con¢;
`
`こ «ド ho 鷲내琦您"••••••••••••••••••••ーー•••••••“••戶■••••••
`(J «Citrate ! 戸
`/
`Eロ * i............./................ z...........
`L ゝ….Ä /\¢eUtlC i /■
`y
`i i * Histidine :
`ヾ
`
`'广
`
`司冬泠= 占 陰¢ 3 『V
`
`Drug Dev Ind Phaim. Early OMme: 1-7
`
`at pH 7 has the ability to form particles due to interactions with
`the Al that is eluted from the glass during storag/l Jn this
`section, we showed the pH £茎mge which has the ability to form
`piarticles in phosphate huffer. Besides, it is 갔Iso reve갔i己d that
`particles containing Â1 form in 갔c己fa比 buffer. The citrate buffer
`solntion, where a decrease in the Al coneentration was not
`shown and pardcies did not form, is thought to keep Al from
`precipitation in the soliidon due to its ch기龍ing ability. In the c차se
`of histidine buffer solution, we were not 갔ble to reve갔i if histidine
`buffer has the ability to form particles, since the Al concentrations
`were very low before storage.
`
`Evaluation of sombHity of abminum oxide and siUca m
`the various buffer solutions
`The solubility of powder of aluminum oxide and silicon dioxide
`(silica), simulated as materials of borosilicate 이잤%, w갔s me갔卯we게
`in the phosphate buffer so Inti on. The powder of aluminum oxide
`or silica was suspended with various pHs of phosphate buffer
`solution ( 20 mM) in plastic tubes and the tube was stored al 25 °C
`for 2 days. Each of the tubes was filte갔te게, then the Al
`concentration for aluminum oxide or Si concentration for silica
`of each filtrate was measured. These coneentrations at various
`pHs are shown in Figure 5, Al concent頒tiöns at neutral pHs were
`lower th갔n both at acidic and alkali pHs. On the other h갔nd.
`Si concentration 2・%：갔higher along with the increase of pH of
`buffer solution. The tendencies of the solubility profile of both
`aluminum oxide and silica in the buffer solutions are considered
`reasonable; since it is w이l-kn。wn that ahiminiim oxide h차s both
`갔cid-soiuble and 갔 1*갔H~soluble species and silica is more soluble
`as the pH increases in other common aqueous solutions. However,
`it is emphasized that the solubility profile of the Al concentration
`was absolutely different from the elution profile of Â1 Ion from
`glass vials (Figure 2), showing the higher pH elutes higher Â1.
`I\irtherniore, each Al。〇ncei血:갔tion was rernarkahly lower th갔n
`one- tenth of Si at pHs greater than '7. On the surface of the glass,
`Â1 is speculated to be forced to leach into the buffer solution in
`accordance with Si elution, especially at neutral pHs.
`The solubility of powder of aluminum oxide and silica ha the
`other three kinds of solution was also measured. Fhe powder of
`aluminum oxide or silica was suspended with pH 5 or 7 of the
`buffer solution (50 niM) in plastic tnbes and the tube was stored at
`25 "C for 6 months. As shown in Figure 6, 갔H of the buffer
`solutions at pH 7 showed a lower Al。〇hc己ntw갔tion than at pH 5.
`On the other hand, for silica, the hnffer solutions at pH 7 showed a
`higher Si concentration than at pH 5. The Al concentration in
`phosphate, citrate, 찬cet或e and histidine bnffer at pH 7 was 〇,07,
`0.31, 0.00 疝게 0.01 ppm, respectively, 갔nd the Si concentrations in
`these buffers were 14.2, 27.1, 6.3 and 8.5 ppm, respectively.
`
`Sä. cone.
`
`14.0 r
`12,0 !-§；3电，蹬3骚璀
`KKO
`(Kf 技■
`1矣A¢。燧械
`Q
`쳔3. U チニ
`
`pH
`
`〇;6
`臨;—………………………… W：………/호……………………………………
`0.2 «.......... 二M<:爲............
`0.0 f J 一*匕E* ご二'.....
`5
`6
`3
`4
`7
`
`pH
`
`9
`
`Figure 2. Al and Si concentrations irt phosphate, citrate, acetate and histidine buffer solutions (50 m.M) in glass vials heated at 105 °C for 24Q min.
`
`CONFIDENTIAL
`
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`
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`

`DOI: 10,3109/03639045.2013.859154
`
`Aluminum elution and precipitation in glass vials 5
`
`Figure 3. Al and Si concentrations in vai'ious buffer solutions (fO or 50mM, pH 7) in glass vials heated at 105 "C for 240 min.
`
`14,0 r
`12,0 H
`IM ■■
`g.o H
`6.0 P
`4,0 ?
`2.0 r
`0,0し
`
`Si cone.
`
`>Fho*!pbate"……………………頒…….
`^OCitrate :
`/
`■-irAcetate :
`>Flistidine ；
`
`/
`
`/
`
`……………………气:广
`
`/■*
`
`〇/
`
`■的 '
`4
`
`A
`5
`
`， ' i'f
`7
`&
`
`S 9
`
`Figure 4. Al and SI concentrations in phosphate, citrate, acetate and histidine buffer solutions (50mM) in glass vial stored at 5 °C for 5 months after
`heat treatment 105 °C for 240 min.
`
`Al. cone.
`
`Figure Q. .Al or Si concentration in suspensions ot akfminifm oxide powder or sihca, respectively. All susperssions (m phosphate buffer, 20mM丿 were
`stored at 25 °C for 2 days.
`
`Al cone,
`} Pho'iphfVe
`鳶(itnue
`£겨 Aeda(e
`曝 Hisikhne
`
`5
`
`pH
`
`7
`
`Figure 6, Al or Si concentrations in phosphate, citrate, acetate arid histidirse biiffer solutions (50rnM), Left: Al concentrations in suspensions of
`aluminum oxide powder. Right: Si concentrations in suspensions of silica. Suspensions were prepared from phosphate, citrate, acetate or histidine
`buffer solution (50 mM) and were stored at 25 "'C for 6 months.
`
`CONFIDENTIAL
`
`ExelaCYSOOl 08736
`
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`
`

`

`6 T. Ogawa et al.
`
`At pH 7, each buffer solution showed different Al and
`Si coneentrations, and the orders of both concentrations were the
`이차痣le (citrate>phosphMe>histidine：>차ceta工e), It is noteworthy
`that the order has some similarities to the eluting study 갔s shown
`in Figure 3 (citrate >phosphate > aeetate > histidine). It is sug­
`gested that those elnting amounts of Al and Si into the buffer
`solutions in glass vials during storage has 차 con，이威with the
`이olu制liiy of both aluminum oxide and 이ilic氣
`On the other hand, 갔t pH 5, it is spE’culafe게 that Si would be
`eluted slightly from the glass vial due to low solnhility of silica,
`regardless of buffer species. As a result, Al would he eluted
`slightly, although all buffer species have r이atively high
`solubilities of alnminum oxide.
`The phenomenon that Al and Si were eluted from glass vials in
`ratios similar to the composition of borosilicate glass although
`Si has high solubility, suggests that the coordination of Al with Si
`is tight and also ^uggesEs that the low solubility of Al contributes
`the ch以nic갔 1 게ür사jil가y of the glass.
`
`Effect of adding Al Ions to the various buffer on the
`particle formation
`In our previous report'气 formation of particles containing Al, P
`and 〇 was observed in phosphate buffer solutions by adding the
`Al ion. As well as phosphate buffer, we £■'¥채luateö whether other
`buffers have a possibility to iat己r갔以 with the Al ion and to form
`precipitate particles.
`One or 0,5 ppm of Al ions were 차dded to the four ki^d이 of
`buffer solution (20n.iM; pH 4,0-11,0 for phosphate, pH 4,0-8.0
`for citral£, pH 4.0-7.5 for 갔cdat。게 pH 5.0-9.0 for histidine),
`and each 女기uti。日 was placed in a plastic vial and then stored at
`5 °C for 1 month. The results of visual inspection are shown in
`Table 3, In the buffer solutions with 0,5 ppm of the Â1 ion,
`particles formed only in the phosphate buffer at the range of
`6.0-9,0; on the other h갔nd, with 1 ppni of the Al ion, particles
`formed not only in phosphate buffer but also in acetate buffer
`(pH 6,5 and 7.0) and histidine buffer (pH 7,0, 7.5 and 8,0), No
`p印力시es were observed in all pHs of citrate buffer. As a resnk of
`the EDX 갔iysis of the particles that were collected from the
`aeetate buffer (pH 6.5) and histidine buffer (pH '7,5), these
`particles eontained at least Al and 〇 (data not shown). Jt is
`d2力©기?: to confirm whether these paHi시es contained aceSte
`and hisü게in。buffer species since EDX does not clearly detect
`carbon (C). However, these results suggest the possibility that
`acetate buffer and histidine buffer form some particles containing
`Ai at a certain pH famge.
`lairthermore, the Al concentration in the filtrate of e차ch buffer
`solution 갔ddi^g 0,5 ppm of the Â1 ion after 1 month stor갔g£' at
`5 "C was measured (Figure '7). For phosphate, acetate and
`histidine buffer, the Al coneentrations decreased from 0.5 ppm
`
`.
`E
`〇
`
`二
`
`〇
`
`出
`
`〇
`
`宀
`
`Drug Dev Ind Phaim. Early OMme: 1-7
`
`at neutral pH. On the other hand, for citrate buffer, A.1
`concentrations did not decrease in all the pHs in this study.
`These results 이ugges£ that each buffer has a different ability to
`maintain Al ion soluble, thus particle formation is observed, at the
`pHs with low solubility for Al complexes. In this study, acegt己
`buffer and histidine buffer solution with additional 0,5 ppm of the
`Al ion did not 이how particles although the A.1 concentration in
`nentral p에3 decreased remarkably. The results suggest that these
`buffer solntioris with 0,5 ppm of the Al ion at 门己ufr갔i pHs might
`have certain panicles which contain AL but the particles are too
`small or too slight to be detected.
`
`Conclusions
`In this stiidy, the ability of eluting the Al ion from glass vi시& and
`tendencies of precipitation containing Al were investigated using
`various pHs of phosphate,갔fe, acetate, 갔nd histidine buffer.
`Through heating, all of the buffers showed that Si and A.1 were
`eluted from glass vials in ratios similar to the composition of
`borosilicate glass at 차ny pH, This suggests that e차ch buffer
`solution has its own eluting ability from glass which is the
`container tor this sohition, depending on the eluting temperature,
`time and its concentration. In addition, during storage after the
`heating, the Â1 concentration of certain pHs of phosphate and
`갔c己论龙 buffer solution decreased, suggesting the fow21 갔tisi of
`particles con£갔畦iing Â1, In citrate buffer, Al did not decrees。over
`time in spite of the high ehition. From the results, where the Al
`solubility profile between aluminum oxide and borosilicate glass
`was different, it is speculated that the Al ion may be forced to
`leach into the buffer solution 갔ccöiöing to Si elution on the
`
`Figure 7, Al concentration of filtrate of phosphate, citrate, acetate and
`histidine buffer solutions (20 mM) with 0.5 ppm of Al ion, stored at 5 °C
`for I month.
`
`Table 3. Results of visual inspection of various buffer solutions (20 mM) with Â1 ion.
`
`Phosphate
`0.5 ppm Al
`1.0 ppm Al
`No
`No
`No
`No
`Detected
`Detected
`Detected
`Detected
`Detected
`Detected
`Detected
`Detected
`Detected
`Detected
`Detected
`Detected
`No
`No
`No
`No
`
`pH
`4.0
`5 Xi
`6.0
`6.5
`7.0
`7.5
`8,0
`9.0
`lOXi
`11.0
`
`Particle (White parii니e) detection
`Acetate
`Citrate
`0.5 ppm Al
`1.0 ppm .Al
`I.Opprn Al
`No
`No
`No
`No
`No
`No
`No
`No
`No
`Detected
`No
`No
`Detected
`No
`No
`No
`No
`No
`No
`
`0.5 ppm .Al
`No
`No
`No
`No
`No
`No
`니 〇
`
`Histidine
`0.5 ppm Al
`1.0 ppm e
`
`No
`No
`No
`No
`No
`No
`No
`
`No
`No
`No
`Detected
`Detected
`Detected
`No
`
`CONFIDENTIAL
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`ExelaCYSOOl 08737
`
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`
`

`

`DOI: 10,3109/03639045.2013.859154
`
`surface of glass vials. When Al ions were added to the buffer
`solutions, phosphate, acetate and histidine buffer showed a
`decrease of Al concentration during storage at 차 neutral range
`of pHs, indicating the formation of particles containing AL
`In conclusion, it is suggested that phosphate buffer solution has
`higher possibility of forming particles containing Al than other
`buffer solutions, since phosphate buffer elutes higher Al th차h
`acetate and histidine buffer and has the ability to interact with Al,
`Citrate buffer, known 갔s a chelating 갔g以兀 does not have" the
`possibility to form particles although it elutes the highest Al out
`of these buffer solutions. Acetate and histidine buffers have a
`lower risk to form particles than phosphate due to the poor eluting
`ability. The results from this $〔uly will provide a number of
`phお‘m갔ceuüc갔 1 世治己おphf*$ working on drug formulation with
`additional information about selecting buffer solutions from the
`perspective of particulate malter fonnation.
`
`Declaration of Interest
`The authors report no conflicts of interest. The authors alone are
`responsible for the content and writing of this article.
`
`References
`L Wang YJ, Chien YW. Sterile pharmaceutical packaging; compati­
`bility and stability. Technical Report No. 5, Washington DC:
`Parente3*ai Drtig Association Inc.; 1983.
`2. White F, Kobeixla M, Chiiamkurfi R. A systematic approach for
`screening glass containers and elastomeflc closures for use with
`parenteral solutions. PDÂ J Ph arm Sci Technoi 2.〇OS;62:157-76,
`3. Sacha GA, Saffeil-Clemmer W, Abrarn K, Akers MJ. Practi