Sumitra A Pillai et al J Pharm Sci
`
`Res Vol 82 2016 103111
`
`ISSN09751459
`
`Journal of Pharmaceutical
`
`Sciences
`
`and Research
`
`wwwjp srphanna
`
`Pharmaceutical Glass Interactions A Review of
`Possibilities
`
`Sumitra A Pillail2 Dhawal Chobisal Dileep UrimilNagasuri Ravindra
`
`2
`
`IPDO Innovation Plaza Dr Reddys Laboratories Ltd Hyderabad 500090 India
`Deparhnent ofPharmacy PAHER University Udaipur 313024 India
`3 Chilkur Balaji College of Pharmacy Hyderabad 500075 India
`
`Abstract
`
`occurrences have observed over
`formulation from years Various untoward
`Glass is used as packaging material for parenteral
`the period of time with glass containers which leads to therapeutic
`failures or even toxicity to the patients Glass has been the
`primary choice for packaging of parenteral
`losses during stability have forced
`formulations unexpected
`degradation or product
`leading to a larger understanding of some of the untoward properties
`many researchers to evaluate the underlying mechanisms
`of glass Oxides of various metal ions viz aluminium arsenic barium iron etc are added in glass to modify its physico
`reasons and
`ions could leach from the glass structure due to several
`chemical properties based on specific requirements Metal
`could lead to generation of particulate matter could cause metal
`ion toxicity or act as catalyst
`to hasten drug degradation
`Delamination or formation of glass flakes
`is one of the major problems currently under high scrutiny by the regulators
`Similarly some molecules have an affinity to adsorb to glass leading to a low potency
`in the administered drug Interaction
`between glass and drug product depends upon compositiontype of glass processing of glass and formulation variables such as
`pH buffer properties of drug sterilization cycles storage conditions etc This review describes
`several possible means of
`interaction of glass and drug product encountered by researchers under a gamut of conditions
`Keywords Glass delamination leachables and extractables particulate matter
`
`Abbreviations
`Al aluminium As arsenic Ba barium Fe iron Ca calcium Mg magnesium Mn manganese Si silica SiO2 silicon
`dioxide B2O3 boron oxide P2O5 phosphorus oxide Ge02 germanium oxide Fe2O3 Ferric oxide Ti203 titanium oxide MnO
`manganese oxide NaC1 sodium chloride KC1 Potassium chloride MgC12 magnesium chloride ZnSO4 zinc sulphate ETAAS
`spectroscopy AAS atomic absorption spectroscopy
`SEM scanning
`electron microscopy
`atomic absorption
`electrothermal
`SEMEDX scanning electron microscopy with energy dispersive Xray spectroscopy EDX energy dispersing Xray analysis FDA
`Food and Drug Administration ICPOES inductively
`coupled plasma optical emission spectrometry
`
`INTRODUCTION
`Wide ranges of packaging material are being used for
`types of dosage forms Selection of packaging
`different
`material mainly depends on
`Type of dosage form
`Mode of application
`Physicochemical
`
`properties
`
`of
`
`formulation
`
`being
`
`review of such reported interactions
`present a consolidated
`of glass with the drug product
`leading
`challenge andor
`a potential or obvious
`
`toxicity to the
`
`to a stability
`
`patient
`
`Glass As pharmaceutical packaging component
`Commercial glasses are an inorganic material mostly
`silicates or mixture of materials that have been heated to a
`molten liquid state then cooled without crystallization to a
`solid state Several metallic oxides have
`the property to
`cool without crystallization eg 5i02 B203 P205 and
`Ge02 These oxides are used as backbone in glass 5i02 is
`the most commonly used oxide including containers
`for
`
`sterile dosage forms 3
`Mechanism of glass formation
`form of
`Silicate glasses are made up of Siat
`tetrahedral
`Si in which each Si atom attached with four oxygen atoms
`has bonding with two Si atoms via
`and each oxygen
`covalent bonds Due to this type of 3D arrangement and
`the melted silicates
`viscosity of
`interactions
`spatial
`increase rapidly during cooling phase which do not allow
`the transition from random structure of
`liquid state
`to
`
`ordered crystalline structure 3 4
`
`packed into
`Physicochemical properties of material being used for
`
`packaging
`
`also vary with the intended
`Regulatory requirements
`like for eg packaging for
`application of the drug product
`regulatory requirements
`parenteral products poses stringent
`is a major concern there pl FDA also
`since sterility
`recommends
`specific quality controls and requirements of
`based on intended use of dosage
`components
`packaging
`forms Glass containers
`have been widely used for packing
`of parenteral preparations
`since many years
`Glass
`containers
`used
`in pharmaceutical
`are widely
`industry but cannot be considered completely inert Various
`could arise when products come in contact with
`exchange
`surfaces
`ion
`glass
`including
`leaching
`precipitation glass dissolution surface layer exfoliation
`
`interactions
`
`and corrosion 2
`
`Various authors have reported different potential leachables
`from glass containers and effect of formulation and process
`factors on total
`leachables The purpose of this article is to
`
`Types Of Glass
`Various minerals are added to improve the industrial
`feasibility and physical properties of the glass Based upon
`
`103
`
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`

`Sumitra A PiIlai et al J Pharm Sci
`
`Res Vol 82 2016 103111
`
`the minerals which are
`
`incorporated glass families are
`
`respectively
`
`the
`
`broadly classified into two 5 6
`A Soda limesilicate glasses or Soda lime glasses
`In this type of glass soda ash sodium carbonate and lime
`are added as a source of sodium
`stone calcium carbonate
`and calcium oxide
`oxide
`to modify
`properties These comprise of 25 by weight Magnesium
`and potassium may be used as their oxides to reduce the
`melting point Soda lime glass has poor chemical
`resistance
`because of chances of leaching of mobile nature of sodium
`and potassium cations
`A1203 is added to improve chemical durability of the glass
`because Ar3 ions are able to form covalent bonds and
`to leaching Fe203 is added to provide
`hence more resistant
`light protection It absorbs ultraviolet wavelengths more
`
`effectively than colourless glass 3
`B Borosilicate glasses
`B203 is used in replacement of some sodium and Ca ions
`Borosilicate glasses have exceptional
`chemical durability
`sudden
`resistance
`high heat
`resistance including
`and
`shock
`thermal
`Borosilicate
`changes
`temperature
`glasses are most commonly used for parenteral containers
`due to its high resistance to thermal processes including
`and terminal sterilization
`depyrogenation lyophilization
`and low alkali extractable Fe203 and Ti203 or MnO can be
`added to produce amber borosilicate glasses for protection
`from ultraviolet
`
`to
`
`light
`
`Mechanism Of Interaction Of Glass With Product
`A Ion exchange
`important mechanism of
`the most
`Ion exchange
`interaction between glass and product Na+ ions which are
`in glass can be replaced by the H30+ ions of the
`present
`solution This reaction is dominant
`in neutral and acidic
`
`is
`
`solutions
`
`B Attack on glass by reactive groups
`Hydroxyl groups and alkaline species present
`in product as
`well as glass itself can attack the glass leads to breaking of
`Si0 bonds This reaction depends upon various factors like
`glass formulation pH of product
`ingredients of product
`etc eg chelating agents are more aggressive toward glass
`because
`the various metal ions out of
`they are able to pull
`the surface It means guidelines
`for selection of glass for
`parenteral products based on pH alone are not sufficient
`C Additional mechanisms
`Process involved in manufacturing of containers has effect
`on composition and physicochemical
`the
`parameters of
`surface eg during manufacturing of ampules and vials the
`temperature of inner surface can exceed the boiling point of
`low boiling point
`ingredients mainly sodium and boron
`During cooling they could condense as sodium borate
`Complete removal of sodium borate from containers may
`not be possible during washing of containers This alkaline
`residue can again affect
`the product by three mechanisms
`residue may react directly with
`Firstly this alkaline
`product Secondly exchange of Na +
`ions with H30+ ions
`loss of H30+ ions in the solution can increase the pH of
`the interaction can
`product Thirdly in extreme
`cases
`the formation of an unstable layer of silica gel
`trigger
`which can slough off as delaminated glassy particles
`
`to
`
`the type all glasses have the potential
`Irrespective of
`into the product
`leach alkali
`related components
`upon
`the stability of that product and
`storage which may affect
`this varies depending on storage conditions type of glass
`used for the storage type and nature of the product being
`stored There is high probability of more leachable content
`coming into the product at higher pH ie pH > 9 Most
`common extractables
`from glass includes silicon sodium
`and boron which take major part in contamination and or
`
`degradation of drug product 4
`Despite of the presence of various inorganic leachables viz
`Al Si B Ba ions etc and interaction with different buffers
`viz acetate citrate phosphate etc glass is most widely
`used
`formulations
`packaging material
`for parenteral
`Glasses can be modified by various techniques to better suit
`the formulation like amber colour glass for photo sensitive
`drugs Selection of glass and the type of modification
`depends upon the formulation and storage
`Some researchers showed that elements of the drug and
`like pH buffers
`formulation
`variables
`etc
`causes
`degradation of glass ultimately contaminating the product
`in patients Amount of
`which leads to adverse effects
`various ions which could leach in the formulation varies
`depending upon the affinity of drug and or excipients
`specific ions
`In this paper we have broadly classified major probable
`mechanisms of drug product contamination by glass into 4
`
`for
`
`categories
`
`A Glass delamination
`B Metal ions interaction
`C Interaction with buffers
`D Adsorption of drugs or formulation components on
`
`glass surfaces
`
`A Glass delamination or generation of glass flakes
`Glass delamination or generation of glass flakes is a major
`
`that use glass vials for
`concern with parenteral products
`their storage and these glass flakes may or may not be
`inspection and the products which contain
`visible for direct
`these glass particles when injected directly may lead to
`embolic thrombotic and other vascular events 7 Possible
`reasons contributing to glass delamination is 8 91 i
`in manufacturing process of glass vials ie
`Differences
`moulding or formation from glass tubing
`higher chance of
`delamination is associated with vials produced by tubing
`process due to the utilization of higher temperatures during
`ii
`Nature of
`formulation being stored
`production
`Alkaline and certain buffer solutions citrate and tartrate
`have higher
`the
`process of
`tendency
`iv
`delamination iii
`terminal
`process
`Presence or absence of ammonium sulfate coating on inner
`surface of glass vials where
`the treatment with sulfur
`enhances the chances of delamination iv Storage duration
`and storage conditions
`Storage at room temperature
`believed to have higher chance of glass delamination over
`cold storage conditions
`process differences and the nature of
`Glass manufacturing
`product seem to be the most dominant factors that enhance
`glass delamination characterized by pH changes
`active
`moiety degradation formation of visible particles
`
`is
`
`and
`
`to
`
`aggravate
`
`sterilization
`
`104
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`

`

`Sumitra A PiIlai et al J Pharm Sci
`
`Res Vol 82 2016 103111
`
`increased extractable levels ultimately affecting the product
`
`quality adversely
`Ronald et al investigated
`the delaminationcorrosion of
`pH of 82
`glass by a pharmaceutical
`product
`having
`Authors have used three type I borosilicate glass vials from
`vendors of which two vials ammonium
`two different
`sulfate treated and the other one untreated were kept
`in
`contact with the product with pH of 82 and the remaining
`were used as a control Vials were stored under 2 different
`temperature conditions 40°C and 30°C Visible particulate
`matter was observed in vials contained product after 30
`days and 8 weeks of storage at 40°C and 30°C respectively
`The particulate matter was found to be glass as identified
`using field emission environmental SEM equipped with X
`ray analysis capabilities NJ
`Richard et al investigated
`the effect of formulation and
`on the delamination process They also
`process variables
`studied the impact of the glass manufacturing process
`on delamination
`and glass
`surface treatment
`supplier
`process They used Type 1 borosilicate tubing vials from 3
`different suppliers total 18 lots and studied the effect of
`formulation pH and moist heat
`terminal sterilization on
`delamination They filled glass vials with Vistide® Injection
`75 mgmL cidofovir
`for Injection USP and to
`in Water
`study the impact of pH solutions pH were adjusted to pH
`60 70 74 80 and 85 with sodium hydroxide or
`hydrochloric acid The filled vials were subjected to either
`three sterilization cycles 123°C for 19 min
`one or
`following which the vials were charged on stability at
`25°C 30°C realtime storage
`and
`40°C
`condition
`They monitored
`testing condition
`accelerated
`delamination by
`particulate matter
`visual
`inspection
`and microscopic methods
`quantification light obscuration
`Vials that were stored at 40°C after autoclaving
`showed the
`presence of glass particles which could be visually seen and
`increased amounts of the same was seen with prolonged
`storage time increasing pH sulfate treatment
`and higher
`number of
`cycles At
`same
`time
`the
`between
`were
`differences
`in the behaviour
`observed
`suppliers and presence or absence of sulfur coating Real
`of
`time stability data indicated
`that presence or absence
`visible glass particles mainly depends on glass type from
`various
`due
`differences
`to
`in processing
`suppliers
`and composition of the glass Visible particles
`conditions
`were found to be containing
`silicon dioxide and sodium
`which are major components of type I glass as determined
`by SEMEDX 10
`Ronald et al
`the factors
`contributing to
`investigated
`delamination which was demonstrated using hippuric acid
`glutaric acid and pemexetred and three type I borosilicate
`types studied were ammonium
`types The vial
`glass vial
`sulfate coated on its inner surface from one vendor and
`two vials sourced from different vendors where one
`other
`type was uncoated and other
`type contained
`dioxide coating Empty vials were initially
`subjected for
`at 250°C and 350°C followed by filling
`depyrogenation
`and sterilization of the filled vials by no or two terminal
`sterilization cycles at 122125°C for 15min The vials posts
`the treatments were stored at 5°C 25°C 40°C and 60°C
`pH measurements
`in pH values
`showed
`a
`decrease
`
`the
`
`sterilization
`
`vial
`
`silicon
`
`compared to initial high pH values >8 and this decrease
`in
`pH was prominent at higher storage temperatures the
`the drop in pH values was not
`authors
`concluded
`that
`test solution but because of
`because of degradation of
`ICPOES analysis revealed the
`degradation of glass itself
`in vials with ammonium
`presence of higher amount of Si
`sulfate treatment
`than that of silicon dioxide treated vials
`followed by uncoated vials Presence of higher amount of
`in the test solutions is indicative
`of
`loss of glass
`Si
`durability or onset of glass delamination which may lead to
`formation of particulate matter or glass flakes The authors
`have finally attributed the delamination to higher pH of
`product and anionic nature of test solutions at this higher
`pH 11
`
`acid
`
`forms e g Zoledronic
`Bisphosphonate
`dosage
`solution can be administered intravenously as an infusion
`These biphosphonate
`dosage forms are highly sensitive to
`di and polyvalent cations especially Ca Ba magnesium
`Al boron
`and
`silicon which are
`in glass
`present
`composition Precipitate formation can be seen as a result
`of reaction between them which affect
`the quality of the
`final product and may cause severe toxicological problems
`Formation of precipitation can be seen upon longer contact
`time of product with glass during storage or during terminal
`the
`sterilization since sterilization process could enhance
`ions from the glass containers There are
`leaching of metal
`some marketed
`formulations which
`are
`lyophilized
`that needed reconstitution
`of bisphosphonates
`products
`before use where chances of precipitation are not absent
`because of presence of trace levels of metal ion impurities
`in saline solutions for infusion preparation
`Alexandra et al took a step to address the current
`and invented a container
`that contains polymeric coating
`internally which is resistant
`towards the bisphosphonate
`the bottle itself can be terminally
`drug solution Moreover
`drug solutions can be
`sterilized by which bisphosphonate
`stored for prolonged time periods 12
`
`issue
`
`B Metal
`ions interaction
`from delamination of glass
`Apart
`surfaces
`important mechanism
`of drug product
`involves
`interaction with metal ions Various metal oxides
`are added in glass during manufacturing process to impart
`and chemical
`These metal
`ions
`physical
`properties
`including Al As Ba Fe etc have
`tendency to leach out
`Some
`and
`the product
`attack
`ion
`important metal
`are discussed here
`
`another
`
`deterioration
`
`interactions
`Aluminium
`Al is the third most abundant mineral on earth and found in
`It has been reported that
`almost every animal and plant
`most adults ingest between 3 and 5 mg Al daily which gets
`excreted in urine However Al is a body constituent
`ingested in higher amount Al
`toxicity was first
`toxic if
`renal
`in patients with chronic
`failure Clinical
`include impaired bone growth in adults and
`development
`in metal
`in neonates
`Parenteral
`delays
`nutrition is a considerable source of Al Therefore in July
`2004 the FDA mandated manufacturers
`to include amount
`of Al
`in label Limit of Al for large volume parenterals
`should be not more than 25
`jigL for small volume
`
`reported
`
`manifestations
`
`it
`
`is
`
`105
`
`

`

`Sumitra A PiIlai et al J Pharm Sci
`
`Res Vol 82 2016 103111
`
`to be different from delamination of glass The particles
`comprised majorly of Al P and 0 however
`these particles
`were
`devoid of Si With raise in temperature of
`the
`formation increased
`these vials upon
`solution particulate
`storage showed decreased amount of Al upon storage at
`5°C for 6 months indicating the presence of Al in particles
`formed in the solution Upon addition of Al chelating agent
`ie citrate there was effective reduction in the formation of
`indicated the presence of interaction between
`the particles
`leached Al from glass vials and phosphate buffer
`in the
`vials This was further evidenced by the formation of white
`upon addition Al ions at concentration of more
`particles
`than 5Oppb
`to the phosphate buffer Sulfur treatment of
`a good mean to
`inner surface of glass bottles provides
`reduce the particle formation Thus great care needs to be
`taken for the storage of dosage forms containing phosphate
`buffer in glass containers 18
`et al studied how the nature of substance can
`Bohrer
`the Al release from glass containers They evaluated
`the pharmaceutical
`for parenteral
`use containing
`products
`salts sodium and potassium chlorides glucose heparin
`and albumin All products were stored in glass and plastic
`containers Al content was determined
`in glass as well as
`containers at different storage time by AAS They
`plastic
`found that glass was the major contributor to Al content
`Besides Al contamination
`highly depended on the nature
`of substance which was in contact with glass surface Table
`1 shows the content of Al extracted by different substances
`after 60 days of storage 19
`
`affect
`
`Table 1 Al extracted by various substances after 60 days
`of storne
`
`Al content ugL
`400
`
`150
`
`500
`
`500
`
`Substance
`
`Salts
`
`Glucose
`
`Albumin
`
`Heparin
`
`SNo
`
`1 2 3 4
`
`sterilization
`
`They found that all products
`containers
`stored in plastic
`contained not more than 20 ugL of Al whereas in glass Al
`reached 1000 ugL and all of them showed an
`content
`increase in Al content with age
`In another study Bohrer et al evaluated the interaction of
`container and chemicals with glass container during heat
`commercial solutions for
`stored 30
`
`They
`nutrition in glass ampoules in contact with
`parenteral
`rubber stopper and plastic container All containers were
`subjected to heat at 121 °C for 30 minutes and Al content
`was determined They found Al content of 157 in glass
`005 in plastic
`and 454 in rubber Also total Al
`and
`released depended on the interaction of chemicals
`containers Various substances showed different Al content
`with glass ampoules and rubber stoppers and the data was
`shown in Table 2 pot
`interaction of glass with chemicals
`They concluded
`that
`and alkalis could
`be explained
`by ion
`salts acids
`exchange properties effect of formulation pH and affinity
`of chemicals especially amino acids for Al pot
`
`106
`
`parenterals the label should state the potential maximum
`In cases where Al intake is
`amount at expiry of the product
`more than 45 pskgd in patients with impaired renal
`the label
`together with premature
`function
`neonates
`they may experience central
`should include a warning that
`nervous system and bone toxicity 1315
`Al can easily get eliminated through urine however higher
`levels of Al pose significant
`risk problems to ones body
`like bone
`in patients with renal
`growth impairment
`impairment and delayed mental development
`in neonates
`in neonates 13
`since the renal system is underdeveloped
`Al
`is a compositional part of glass and added during its
`as aluminium oxide and sometimes this may
`manufacture
`get leached into the product which is being stored in it and
`Few studies
`can contaminate
`the product
`the
`report
`presence of Al in parenteral nutrition due to storage in glass
`containers Content of Al increases with storage time and
`also depends on the nature of the substance in contact
`like
`heparin and albumin Product pH values at extremes also
`the Al release
`adversely affect
`et al evaluated
`the amount of Al
`leached in
`Bohrer
`parenteral nutrition containing amino acids They used 19
`amino acids and commercial nutrition formulation to check
`the effect of binding of amino acids from Al of glass
`material They stored solutions of amino acids in type II
`glass flasks and Al content was measured periodically for
`by ETAAS They
`400
`concluded
`the
`days
`that
`contamination with Al was observed with cysteine cystine
`aspartic acid and glutamic acid only Leaching of Al from
`glass because of amino acids mainly depends upon stability
`of formed Al amino acid complex ie higher the stability
`of complexes higher the ability of amino acids to release Al
`16
`Toni et al studied the release of Al from borosilicate
`glass vials and the effect of different buffers like phosphate
`citrate acetate and histidine buffer at different pH on the
`and precipitation of Al The
`release behaviour
`vials
`showed the presence
`different buffer solutions
`containing
`of Al and Si upon heating at any pH which demonstrated
`the Al from glass
`the ability of all buffers in extracting out
`and which depended upon
`containers
`concentration
`of
`solution time of contact and storage temperature Higher
`amounts of Al and Si were observed in glass vials with
`citrate buffer and in comparison to this lower amounts were
`and histidine buffers
`observed with phosphate
`acetate
`Upon storage particle formation was observed in phosphate
`and acetate buffers while no particulate matter was seen
`with citrate buffer which was attributed to its chelating
`property This was supported by the reduction in Al content
`acetate and histidine buffer upon addition of
`in phosphate
`Al ions during storage At the end the authors concluded
`the possibility of formation of Al containing
`that
`was much higher in phosphate buffer
`other buffer solutions 17
`In an interesting study by Tom et al authors
`the
`of
`investigated
`inorganic
`characteristics
`particles
`formed in phosphate buffer filled glass vials Upon storage
`of the glass vials which are compendially recommended
`for injectable products filled with phosphate buffer visible
`particles were seen and authors deliberated these particles
`
`particles
`
`in comparison
`
`to
`
`have
`
`

`

`Sumitra A PiIlai et al J Pharm Sci
`
`Res Vol 82 2016 103111
`
`Table 2 Value of Al content
`
`Substances
`
`Leucine ornithine and lysine solutions
`Solutions of basic phosphates and bicarbonate
`
`Cysteine aspartic acid glutamic acid and cystine solutions
`
`SNo
`
`1 2 3
`
`in different products stored in contact with glass ampoules and nibber stopper
`Al content ugL
`20
`
`Container
`
`Glass ampoules
`
`Glass ampoules
`
`Rubber stoppers
`
`1500
`
`500
`
`is clear
`
`that glass can be a
`Based on available literature it
`source of Al when products
`stored in glass
`are being
`the extent of contamination may vary
`containers
`but
`depending upon the type of product eg liquid form or
`form
`powder
`Marlei et al investigated
`the Al contamination in liquid
`and lyophilized
`forms of Erythropoietin which were
`contained in glass bottles sealed with rubber closures The
`authors have found that glass and rubber were the sources
`of Al contamination after storage of formulation in contact
`with glass as well as rubber at 4 ± 2°C As determined by
`spectrometry higher Al contamination
`atomic absorption
`was
`found in glass vials with liquid formulation
`as
`compared to glass vials containing lyophilized form of the
`product When stored in liquid form citrate and phosphate
`buffers extracted most of the Al present as contamination
`source of Al
`The
`container
`a
`glass
`fact
`that
`is
`contamination can be supported by 19 fold increase in Al
`contamination after reconstitution in the same vials in 12
`months
`contamination before
`compared with the
`as
`reconstitution Moreover Al contamination after one month
`lyophilized form is more than the
`of reconstitution of
`contamination in lyophilized form after storage for 2 years
`in glass vials The authors have concluded that
`lyophilized
`its solution form
`form of erythropoietin is preferred over
`for patients with chronic kidney disease 21
`Nakamura et al studied minodronic acid formulations
`and
`compositions and their stability
`different
`having
`tendency to generated particles upon storage at 60°C for 4
`weeks Upon characterization the formed precipitate was
`found to be a complex between minodronic acid and Al
`leached from the glass of the ampoules
`ions apparently
`The best protection in terms of stability as well
`as
`matter was
`inhibition
`of
`afforded
`to
`particulate
`formulations buffered by citric acid and tartaric acid citrate
`the two particularly providing
`buffer was better amongst
`to 5 where no
`results at a solution pH of 3
`optimal
`particulate generation was observed 22
`the same authors
`demonstrated
`Further
`formulation containing 05 mgml minodronic acid 40 mM
`pH 45 citrate and sodium chloride stored in flint glass
`at 25 40 50 and 60 degrees C showed
`ampoules
`at 25C but not at higher
`particulate matter generation
`particulate matter by
`temperatures Analysis of
`the
`SEMEDX revealed that
`the particulate matter contained Al
`and phosphorus Storage in plastic
`and 5i02
`containers
`treated glass ampoules did not show the rise in number of
`the particulate matter A spike of minodronic acid solution
`with Al ions led to the particulate
`generation proving the
`and Al ions to
`interaction of minodronic acid molecules
`form a complex and resulting in particulate matter Regular
`ampoules were found to be the source of leached Al 23
`
`that
`
`a
`
`liquid
`
`Arsenic
`
`Transparency
`
`glass
`
`suitable
`
`ulceration
`
`presence of As V in higher amount
`
`This
`
`is one of the great properties which make
`and storage of many of
`for packaging
`products mainly in case of parenteral
`pharmaceutical
`dosage forms To make glass more transparent
`fining
`agents like arsenic oxide III may be added This added
`arsenic oxide may get released out of glass into the product
`which is being
`stored
`under
`certain
`conditions
`like
`sterilization temperature and nature of substance Released
`As can contaminate
`and upon intravenous
`the product
`administration it severely induces the toxic effects like skin
`cancer mucosal membrane
`damage
`skin
`etc 24 Allowable limit of As species
`in
`keratosis
`products for IV administration should be less than or equal
`to 01 mgL
`et al in a study investigated
`the release of As
`Bohrer
`both AsV and AsIII from glass containers by action of
`intravenous nutrition formulation constituents after heating
`the ampoules at 121°C for 30min using hydride generation
`atomic absorption spectrometry HG AAS Before heating
`the ampoules containing nutrition formulation As content
`of both the substances used in formulation as well as glass
`ampoules was determined
`and the results
`showed
`the
`in glass than As III
`that during heating As is getting
`study indicated
`and the
`from the
`containers
`solution
`released
`glass
`composition decides the type and amount of As species
`getting released Ampoules containing water for injection
`and solutions of NaC1 KC1 phosphates
`indicated
`the
`presence of AsV only whereas
`ampoules
`containing
`amino acids glucose gluconate
`and vitamins showed
`higher concentration of AsIII since these can reduce the
`AsV to AsIII due to their reducing behaviour 25
`the presence of different As
`et al evaluated
`Bohrer
`species arsenite and arsenate in several of the commercial
`solutions of amino
`formulations that
`included
`parenteral
`acids salts vitamins and lipids and the measurements of
`As species were done using hydride generation
`atomic
`and results of which showed the
`absorption spectrometry
`presence of As in both the forms in all
`formulations
`Presence of higher As contamination with varied ratios of
`AsVAsIII was evidenced in Calcium gluconate sodium
`bicarbonate heparin and vitamin solutions Interestingly
`the vials with water for injection and salt solutions showed
`only the presence of AsV species but
`the ones with
`and glucose
`showed
`solutions of vitamins gluconate
`AsIII primarily the reason being the conversion of AsV
`to AsIII
`since these sugars are
`reducing
`was
`Evidence
`by
`phenomenon
`demonstrated
`of
`the
`complete absence of As III
`in pure water and sodium
`for 15 minutes and
`chloride solution upon autoclaving
`the same predominantly in solutions with
`occurrence of
`upon autoclaving 26
`reducing substances
`
`in nature
`
`107
`
`

`

`Sumitra A PiIlai et al J Pharm Sci
`
`Res Vol 82 2016 103111
`
`in comparison to
`
`to
`
`storage
`
`significantly
`
`in amber color ampules
`higher extent
`clear ampules The authors found that
`the degradation by
`oxidation was a free radicalmediated process which was
`being enhanced by the presence of metal ion contaminants
`The source of these metal ion impurities was found to be
`the amber coloured glass ampoules which contained higher
`than the clear glass ampules Addition of 01
`Fe content
`wv edetate
`disodium prior
`rate 31
`reduced the decomposition
`Kassem et al and Lipper et al reported similar kind of
`degradation of ascorbic acid and thimersol
`in presence of
`metalions upon storage in amber coloured glass ampoules
`30 32 33
`Reed et al determined
`degradation of
`the photochemical
`citrate buffered formulations of phenyl ether based drug
`sensitive when
`which were found
`to be light
`to ICHdefined
`though
`conditions
`the
`light
`molecule
`as well as the components of the formulation
`were not absorbing in the 300700 nm exposure regions
`The pathway
`for degradation was proven to be interaction
`between Fe+2 and dissolved oxygen to form superoxide
`radical when then protonated in water to generate hydoxy
`recombined
`radicals which eventually
`peroxyl
`to give
`reacted with Fe to give hydroxyl
`hydrogen peroxide that
`
`according
`
`studied
`
`radicals
`
`These
`
`hydroxyl
`
`react with drug to
`radicals
`Fe levels
`in the
`produce
`phenol
`degradate
`present
`formulation were contributed by the raw materials used in
`the formulation as well as the glass vials the amount of Fe
`for product being stored in glass increases with storage
`time and it could be due to Fe leaching from borosilicate
`glass vials The combination of citrate from the formulation
`to reduction of Fe Thus major
`and light
`contributed
`contributors to the observed photosensitivity were the
`citrate buffer parts per billion ppb levels of Fe oxygen
`and light exposure level At a particular Fe concentration
`was
`formation
`of
`primary
`photodegradate
`linearly
`to the amount of light exposure Moreover at
`proportional
`a fixed amount of light exposure photodegradate
`formation
`to the amount of
`was nearly linear proportional
`through 200 ppb levels 34
`Quarry et al evaluated the degradation of compounds of
`the 4 5epoxymorphinan series eg naloxone nalbuphine
`and oxymorphone which are known to be light sensitive in
`glass HPLC vials
`solution when
`in amber
`stored
`compounds of the same
`Investigation of the degradation
`lot of Naloxone HC1 Injection 002 mgml at
`laboratories in amber
`vials and
`glass
`a Fe+3
`proved that
`vials wrapped with foil
`colourless
`leaching from the amber glass vials because of Fe oxide
`was catalysing
`the degradation Similar degradation was
`observed in naloxone nalbuphine and oxymorphone that
`The author
`were stored in amber glass
`conclude
`that
`though amber glass are routinely used to pr