J Pharm Pharmaceut Sci (www. cspsCanada.org) 9 (3): 398-426, 2006
`
`the excipients rather than degradation of the
`active pharmaceutical ingredient by standard
`routes such as oxidation, hydrolysis, photolysis
`or thermolysis. This low percentage however
`illustrates the low risk associated with these
`dosage
`forms
`investigated.
`It may be
`concluded that when considering the safety
`and efficacy of liquid dosage forms prepared
`extemporaneously, it is thus important to
`consider not only the stability of the drug
`substance but the entire formulation.
`
`INTRODUCTION
`
`The lack of commercially available oral liquid
`dosage forms is an ongoing problem in many
`practice settings. A pharmacist
`is often
`challenged to provide an extemporaneous oral
`liquid for (i) paediatric patients; (ii) patients
`who are unable to swallow solid dosage forms
`such as tablets or capsules; (iii) patients who
`must receive medications via nasogastric or
`gastrostomy tubes; and (iv) patients who
`require non-standard doses that are more easily
`and accurately measured by using a liquid
`formulation (1-10). It is common practice for
`these liquid dosage forms to be prepared from
`a commercially available oral solid dosage
`form by simply crushing tablets or opening a
`capsule and the subsequent addition of water
`or juice. However these dosage forms can
`become complex (2) due to the addition of
`excipients and while these measures are taken
`to improve compliance and stability of the
`extemporaneously prepared product, there are
`often limited data to support the stability or
`bioavailability of the final liquid dosage form,
`where potential
`interactions between
`the
`vehicle,
`preservative,
`buffering
`agent,
`flavouring agent, levigating agent, suspending
`agent, viscosity enhancer, storage container
`and the modified commercial product have yet
`to be established.
`first
`the
`represents
`This
`review
`comprehensive summary of
`liquid dosage
`forms prepared from commercially available
`tablets and illustrates the low risk associated
`with these products if cognisance is taken,
`
`_____________________________________
`
`Corresponding Author: Beverley D Glass, Chair of
`Pharmacy School of Pharmacy and Molecular Sciences,
`James Cook University, Douglas Campus, AUSTRALIA,
`Email: Beverley.Glass@jcu.edu.au
`
`
`
`Stability considerations in liquid
`dosage forms extemporaneously
`prepared
`from
`commercially
`available products.
`
`Beverley D Glass1 and Alison Haywood2
`
`1School of Pharmacy and Molecular Sciences,
`James Cook University, Townsville, QLD,
`Australia.
`2School of Pharmacy, Griffith University, Gold
`Coast Campus, QLD, Australia.
`
`Received October 10; 2006; Accepted December 13;
`2006, Published December 14, 2006.
`
`in community and
`The pharmacist, both
`hospital pharmacy practice, is often challenged
`with the preparation of a liquid dosage form
`not available commercially for paediatric
`patients, those adults unable to swallow tablets
`or capsules and patients who must receive
`medications via nasogastric or gastrostomy
`tubes. Recognising the lack of information
`available to healthcare professionals, a general
`discussion of the various parameters that may
`be modified in preparing these dosage forms
`and a tabulated summary of the dosage forms
`presented in the literature is described, which,
`although
`not
`exhaustive, will
`provide
`information on the formulation and stability of
`the most commonly prepared extemporaneous
`liquid dosage forms. An extensive survey of
`the literature and investigation of 83 liquid
`dosage
`forms
`revealed
`that
`stability
`considerations were of concern for only 7.2 %
`of
`these
`liquid
`dosage
`forms,
`extemporaneously prepared from the following
`commercially available products: captopril,
`hydralazine
`hydrochloride,
`isoniazid,
`levothyroxine
`sodium, phenoxybenzamine
`hydrochloride and tetracycline hydrochloride.
`Inclusion of the antioxidant, sodium ascorbate
`in the liquid dosage form for captopril resulted
`in improved stability at 4ºC. Hydralazine
`hydrochloride,
`isoniazid
`and
`phenoxybenzamine
`hydrochloride
`were
`adversely affected due to interactions with
`excipients in the formulation, while the effect
`of the preservative in lowering the pH in a
`levothyroxine sodium mixture resulted
`in
`decreased stability. Interestingly, the instability
`in these formulations is primarily due to
`interactions between the drug substance and
`
`
`
`
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`
`
`
`the active pharmaceutical
`not only of
`ingredient but all those ingredients contributed
`to the formulation as excipients from the
`commercially used product.
`
`ORAL LIQUID PREPARATIONS
`
`liquid preparations for paediatric
`Oral
`patients
`
`Studies (2, 7, 9, 11-14) have identified that the
`preparation of
`liquid
`formulations
`for
`paediatric patients is both a daily experience
`and challenge for the pharmacist and paediatric
`health care provider. Appropriate formulations
`for administration to children exist for only a
`minority of commercially available drugs and
`the need for extemporaneously compounded
`formulations is escalating due to the release of
`many new drugs formulated for adults but with
`expected use in children (7, 9, 11). Children
`require
`titratable
`individualised doses
`in
`milligrams per kilogram of body weight and
`most children under six years of age cannot
`swallow tablets (15, 16).
`A survey (14) into the informational
`needs of hospital compounding pharmacists
`providing pharmaceutical care to paediatric
`patients at 57 sites in the USA and Canada
`listed 76 extemporaneously prepared drug
`formulations as having adequate stability data,
`109 formulations for which improved stability
`data were requested, and an additional 103
`drug formulations prescribed by paediatricians
`that had no compounding or
`stability
`information available.
`There are many reasons for the lack of
`commercially
`available
`paediatric
`formulations. The overall size of the paediatric
`market
`is much smaller
`than for adults,
`especially for common diseases such as
`hypertension. The industry is thus reluctant to
`commit resources to seek labelling for infants
`and children
`(unless a disease occurs
`exclusively or frequently in the paediatric
`population), since the formulation has to have
`been adequately studied in paediatric patients.
`Therefore, additional costs, limited financial
`returns, delay in marketing for adults, and
`perceived greater legal liability and regulatory
`requirements are impediments to developing
`and marketing a paediatric drug formulation
`(7, 17). It is encouraging to note, however, that
`according to a recent European memorandum,
`pharmaceutical manufacturers may be given
`
`
`
`to manufacture and distribute
`incentives
`medicines for a common paediatric market (14,
`18). The FDA (Food and Drug Administration
`Act) Modernization Act (FDAMA) of 1997
`provides incentives for the development and
`marketing of drugs for children. Under this
`Act, the FDA would waiver user fees for
`supplemental
`application
`for
`paediatric
`approval of new drugs already approved for
`use
`in adults.
`In addition,
`the market
`exclusivity period would be extended by six
`months for new drugs if the pharmaceutical
`industry can demonstrate health benefits in the
`paediatric population (18).
`Tablets are often cut into smaller
`segments (halves or quarters) in the pharmacy
`or on the ward to obtain appropriately sized
`dosage units for children, however a major
`concern is that segments from tablets cannot be
`cut with great accuracy of dose (12, 19-21).
`McDevitt et al (20) conducted an extensive
`analysis on the ability to split a 25-mg
`hydrochlorothiazide tablet accurately by 94
`volunteers. Of the 1752 manually split tablet
`portions, 41.3 % deviated from ideal weight by
`more than 10 % and 12.4 % deviated by more
`than 20 %. Gender, age, education, and tablet-
`splitting experience were consistently found
`not to be predictive of accuracy. Most subjects
`(96.8 %) stated a preference for commercially
`produced, lower-dose tablets, and 77.2 % were
`willing to pay more for them. The issue of cost
`containment in the treatment of hypertension
`has seen many physicians prescribing larger
`dosages of drugs and then instructing patients
`to split the tablets to receive the correct dose,
`and some health maintenance organisations are
`providing tablet splitters to patients while
`dispensing larger than prescribed doses (20).
`Modification of the commercial medication in
`this manner may be less expensive in the short
`term, but it has not been proven to be
`financially or medically effective and is of
`particular concern for drugs with steep dose-
`response
`curves or narrow
`therapeutic
`windows. The most appropriate device for
`splitting tablets is a further issue. Horn et al
`(19) conducted a study on captopril, clonidine,
`amlodipine, atenolol, carbamazepine, and
`setraline tablets to assess the reproducibility of
`tablet
`splitting
`using
`two
`different
`commercially
`available pill
`cutters, by
`examining the weight variation between the
`tablet parts (halves and quarters). Their results
`showed an
`inability
`for
`tablets
`to be
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`
`
`
`reproducibly split by both devices and it was
`suggested that paediatric practitioners and
`pharmacy administrators investigate alternative
`dosage forms, such as the extemporaneous
`compounding of solutions, when small dosages
`are required for paediatric patients.
`It has been estimated that more than 40
`% of doses given in paediatric hospitals require
`compounding to prepare a suitable dosage
`form (9) since crushing a
`tablet and/or
`sprinkling the contents of a capsule over food
`or mixing in a drink may lead to errors in
`preparation or delivery of doses (14).
`Occasionally extemporaneous powders
`have been prepared by redistributing
`the
`powder from commercially available crushed
`tablets or opened capsules into smaller strength
`capsules or powder papers/ sachets, sometimes
`after dilution with lactose or similar material
`(12). This practice has been reported to be
`inflexible and time consuming (15, 22, 23) and
`further, usually requires
`the caregiver
`to
`reconstitute the powder form of the drug into a
`liquid dosage form immediately prior to drug
`administration, with
`the potential for
`the
`caregiver to be unable to accurately prepare
`and administer each dose (24, 25).
`Another practice seen in paediatric
`care is to use injectable solutions for oral
`administration (13, 26). This is generally cost-
`prohibitive (27) and presents with many
`problems including the following: (i) drugs
`and/or vehicles may be mucosal irritants,
`vesicants, nauseants, or cauterants; (ii) drugs
`may undergo extensive first-pass metabolism
`or may have poor bioavailability after oral
`administration (e.g. cefuroxime and enalapril)
`(7); (iii) drugs and/or vehicles suitable for
`injection may be unpalatable; (iv) excipients
`included in the formulation may have toxic
`effects when cumulative oral ingestion is
`considered; and (v) co-solvents used in the
`commercial formulation may be diluted when
`mixed with syrup or water, thus allowing the
`drug to precipitate (13).
`In most cases the pharmacist will
`therefore prepare an oral liquid dosage form
`with
`the active
`ingredient dissolved or
`suspended in a simple syrup or sorbitol
`mixture (7, 12, 18, 28). Since pure crystalline
`powders of drugs are not usually accessible to
`pharmacies,
`the
`active
`pharmaceutical
`ingredient
`(API)
`is often obtained by
`modifying a commercially available adult solid
`dosage form by crushing a tablet or opening a
`
`
`
`is formulated for
`capsule. When a drug
`paediatric use, several factors unique
`to
`paediatrics must be considered such as the
`immaturity of the intestinal tract and the
`subsequent
`influence on gastrointestinal
`absorption, and the fact that seriously ill
`neonates are often fluid restricted, limiting the
`volume of medications that can be received.
`Additives, including preservatives and sugar
`must be chosen carefully. Patients who are
`fructose intolerant have had significant adverse
`effects from sorbitol and there is a link
`between chronic use of sugar sweetened
`medication
`and
`dental
`caries
`(11).
`Formulations may also contain preservatives;
`an excipient considered to be largely inert in
`adults, however, may lead to life threatening
`toxicity in paediatrics when multiple doses of
`medications with the same preservative are
`employed. This is particularly the case with
`benzyl alcohol and benzoic acid (11).
`The physical, chemical, microbial and
`therapeutic stability of the above paediatric
`extemporaneous preparations may not have
`been undertaken at all. This coupled with the
`increased
`potential
`for
`calculation
`or
`dispensing errors may prove the practice of
`modifying commercially available products to
`be extremely unsafe. Although information
`(29-31) is available detailing extemporaneous
`formulations for parenteral and oral use,
`however, only some of the formulations have
`documented stability data.
`
`liquid preparations
`Oral
`residential aged-care facilities
`
`Many people in aged-care facilities have their
`medications modified
`for
`ease
`of
`administration. For example, nurses at nursing
`homes routinely use a mortar and pestle to
`crush oral solid medications for elderly
`patients with swallowing difficulties and
`sprinkle the crushed medication over the food
`(1, 32). While this practice aims to ensure
`residents receive necessary medications, there
`are also potential problems with this practice
`(4). Modifying a commercially available
`medication may lead to (i) increased toxicity,
`e.g. crushing an extended-release solid dosage
`form leads to dose dumping; (ii) undesirable
`side effects; (iii) decreased efficacy, e.g.
`crushing an enteric coated tablet may result in
`destruction of the active ingredient in the
`acidic environment of
`the stomach; (iv)
`
`for use
`
`in
`
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`
`
`
`in poor patient
`resulting
`unpalatability,
`compliance; (v) instability of the medicine,
`affecting the rate of drug absorption; and (vi)
`create potential hazards to health care workers,
`e.g. crushing cytotoxics (1, 4, 5).
`The processes by which medicines are
`modified in these facilities are also a cause for
`concern. In a study in South Australia (5), at
`least one medication was modified in 34 % of
`the
`1207
`occasions
`of medication
`administration observed within ten residential
`aged-care facilities. In all occasions where
`more than one medicine was modified, they
`were crushed together within the same vessel.
`In 59 % of occasions where the same vessel
`was shared amongst residents, the vessel was
`not cleaned between residents and in 70 % of
`cases where medicines were modified,
`spillage, and thus potential loss of dosage, was
`observed. The administration of the crushed
`medicines then poses a further concern, as in
`the majority of cases, the crushed medication
`was mixed in a small medication cup with a
`soft medium such as jam, custard or fruit. This
`raises questions as to the physicochemical
`stability of the active ingredient in the food
`medium, especially in the case of acid-labile
`active ingredients. In 2 % of the observations,
`the crushed medications were sprinkled over
`the resident’s meal, questioning the dosage (5).
`In a study (6) involving 540 nurses (out of a
`potential 763) employed in nursing homes in
`England, 40 % admitted to crushing tablets
`every drug round, 29 % every day and 12 % at
`least every week. All of the tablets that the
`nurses admitted to crushing were available to
`be administered by other routes, in dispersible
`formulations or as a liquid. Reasons for
`crushing tablets were listed as “the GP tells me
`to” (58 %) and that the GP would be concerned
`about
`the cost of changing
`to a
`liquid
`formulation (60.9 %). Although the cost of
`alternatives is a justifiable concern, it must be
`viewed in the contexts of patient safety and
`professional liability (6).
`The practice of crushing tablets may
`breach legal and professional requirements
`(33, 34). The important legal issues related to
`the act of tablet crushing and capsule opening
`are outlined by Wright (6) as follows: (i) the
`opening of a capsule or crushing of a tablet
`before administration will in most cases render
`its use to be “unlicensed”. Consequently the
`manufacturer may assume no liability for any
`ensuing harm that may come to the resident;
`
`
`
`and (ii) under the Medicines Act 1968 only
`medical and dental practitioners can authorise
`the administration of “unlicensed” medicines
`to humans. It is, therefore, strictly illegal to
`open a capsule or crush a tablet before
`administration without the authorisation of the
`prescriber. When a medicine is authorised to
`be administered “unlicensed” by a prescriber, a
`percentage of liability for any harm that may
`ensue will still lie with the administrating
`nurse. The balance of this liability would be
`assessed in a court of law on an individual case
`basis (6).
`
`Oral liquid preparations for use in enteral
`feeding
`
`There is a growing interest in enteral feeding
`as a means of delivering medications and new
`feeding tubes are being designed in order to
`share the capacity for medication delivery (33).
`Although the newer feeding tubes share the
`capacity for medication delivery, their use for
`the administration of drugs may
`induce
`intolerance and/or result in less than optimal
`drug
`absorption,
`for
`example:
`(i)
`the
`bioavailability of the drug may be altered,
`resulting
`in
`unpredictable
`serum
`concentrations or tube occlusion; (ii) drugs
`may bind to the enteral feeding tube, reducing
`drug absorption; (iii) crushed tablets can block
`the enteral tube requiring it to be replaced and
`(iv) there may be interactions between the feed
`and certain drugs, such as the metal ions in
`antacids binding to the protein in the feed and
`subsequently blocking the tube (33, 35). The
`British Association for Enteral and Parenteral
`Nutrition (BAPEN) has published guidance on
`the safe administration of medicines via enteral
`feeding tubes (36). Liquid rather than solid
`medicines should always be administered to
`patients being fed by the enteral route.
`
`OF
`REVIEW
`LITERATURE
`EXTEMPORANEOUSLY
`PREPARED
`ORAL LIQUID DOSAGE FORMS
`
` review protocol was developed with data
`identified
`from MEDLINE, EMBASE,
`Informit, reference texts related to the field,
`reference lists of articles and abstracts from
`conference proceedings. Searches were current
`as of September 2006.
`This review presents 83 examples
`(Table 1) of oral liquids in practice, prepared
`
` A
`
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`
`
`
`by modification of commercial medications,
`including the reasons, methods, excipients and
`packaging for the extemporaneous preparation
`and the outcome of the chemical and physical
`stability
`studies conducted. This
`review
`considers only those liquid dosage forms
`prepared from commercially available dosage
`forms as this is the situation most commonly
`encountered in the practice of pharmacy. Table
`2 shows the contents of the various proprietary
`vehicles
`utilised
`to
`prepare
`the
`extemporaneous mixtures shown in Table 1.
`Only those preparations that included
`chemical stability assessment via a stability-
`indicating
`high
`performance
`liquid
`chromatography
`(HPLC) method were
`reviewed and drugs were considered stable if
`they retained ≥ 90% of the initial drug
`concentration. The reason for this is best
`demonstrated by the results of study by Carlin
`et al (37) on the stability of isoniazid (INH) in
`INH syrup. Hydrazine, a known carcinogen
`and one of INH’s principal degradation
`products, is also an amine and thus not
`distinguished
`from
`parent
`INH. The
`inadequacy of the then current compendial
`assay in failing to distinguish between INH
`and hydrazine prompted Carlin et al (37) to
`assess the stability of commercial INH syrup
`stored under various conditions over a 4-month
`period. At 0 ºC, no hydrazine was detected
`over
`the
`storage
`period,
`however,
`decomposition to hydrazine was observed at
`ambient temperature with a 5.5 – 6.0 fold
`increase
`in decomposition rate when
`the
`storage temperature was raised to 40 ºC. The
`formation of hydrazine was linear with time.
`Where more
`than one
`stability-
`indicating study had been conducted for each
`API and demonstrated similar results, only the
`most recent study is reported in the table. Prior
`studies to those presented in Table 1, that (i)
`include chemical stability assessment and (ii)
`are prepared by modifying an existing
`commercial medication, have been performed
`on the following API’s: acetazolamide (38,
`39), allopurinol
`(40), azathioprine
`(40),
`baclofen (41), bethanechol chloride (42, 43),
`captopril (44), cisapride (45, 46), clonazepam
`(47), diltiazem hydrochloride (48), enalapril
`maleate (49, 50), famotidine (51), flecainide
`acetate (52), flucytosine (53, 54), hydralazine
`hydrochloride
`(55), hydrocortisone
`(56),
`itraconazole (57), labetalol hydrochloride (58),
`metoprolol tartrate (59), metronidazole (60),
`
`
`
`midazolam (61-64), mycophenolate mofetil
`(65, 66), nifedipine (67), norfloxacin (68),
`omeprazole (69), procainamide hydrochloride
`(70, 71), pyrazinamide (72), rifampin (73-75),
`sotalol
`(76), spironolactone
`(59, 77-79),
`tramadol (80), ursodiol (81) and verapamil
`hydrochloride (82).
`in
`The highlighted (shaded) areas
`Table 1 indicate those preparations (6 of the
`total 83) with stability concerns and are further
`reviewed in the discussion.
`
`STABILITY
`OF
`DISCUSSION
`IN
`THE
`CONSIDERATIONS
`PREPARATION OF ORAL LIQUID
`DOSAGE FORMS
`
`Of the liquid dosage forms reviewed in the
`literature, stability was considered
`to be
`unfavourable for only 6 of the 83 dosage forms
`– a small percentage, illustrating that there is
`minimum risk associated with these dosage
`forms and that pharmacists taking cognisance
`of various factors such as drug stability,
`mechanisms and routes of degradation, and
`potential interactions with excipients in the
`tablets and/or capsules utilised
`in
`the
`formulation are further able to minimise the
`risk involved. The individual dosage forms
`displaying stability concerns are discussed
`below.
`
`Captopril liquid dosage forms
`
`The formulation of captopril, used to treat
`hypertension and congestive heart failure in
`infants and young children, in a liquid dosage
`form from commercially available tablets, has
`proved problematic with many and varied
`results reported in the literature (77, 138-140).
`Utilising stability data in the literature that
`captopril oxidation yields captopril disulphide,
`Nahata et al (44) decided, in addition to
`investigating the stability of captopril in water
`and syrup, on the inclusion of the antioxidant,
`sodium ascorbate in distilled water. For these
`researchers
`the
`application of
`existing
`knowledge on the susceptibility of captopril to
`oxidation allowed them to extend the shelf-life
`of the extemporaneously prepared captopril
`mixture (in distilled water) from 14 days at 4
`ºC and 7 days at 22 ºC to 56 days and 14 days
`respectively (in distilled water and sodium
`ascorbate). This confirms the need for the
`pharmacists to utilise their understanding of
`
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`
`Table 1. Oral liquid dosage forms prepared by modification of commercial medications
`
`
`J Pharm Pharmaceut Sci (www. cspsCanada.org) 9 (3): 398-426, 2006
`
`Excipients
`
`Packaging
`
`Stability study data
`
`Stability considerations
`
`API with reference
`
`
`
`Acetazolamide
`(53)
`
`Extemporaneous
`modification
`How? Why?
`1a
`2d
`
`Optimum pH 4-5.
`
`
`
`Stability in the vehicles
`tested may be partly
`attributed to the drug’s
`poor aqueous solubility.
`Mixtures prepared from
`pure powder were more
`stable than those
`prepared from tablets.
`
`21 mg/mL suspension
`was not stable when
`stored at 4 ºC; white
`crystals formed that were
`not redispersible.
`
`
`
`
`
`
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`Ora-Plus; and cherry syrup.
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`Ora-Plus; and cherry syrup.
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`Ora-Plus; and cherry syrup.
`
`3c (amber) 4a. 25 mg/mL mixture stored
`in the dark was stable for 60
`days at 5 and 25 ºC.
`3c (amber) 4a. 20 mg/mL mixture stored
`in the dark was stable for 60
`days at 5 and 25 ºC.
`4a. 1 mg/mL mixture stored
`in the dark was stable for 60
`days at 5 and 25 ºC.
`
`3c (amber)
`
`Allopurinol (53)
`
`1a
`
`Alprazolam (83)
`
`1a
`
`Amiloride
`hydrochloride (84)
`
`1a
`
`
`2d
`
`2d
`
`2d
`
`2 vehicles: Glycerin BP 40 %
`w/v and sterile water;
`Glycerin BP 40 % w/v, sterile
`water and 0.1% Compound
`hydroxybenzoate solution
`APF.
`
`Aminophylline
`(85)
`
`1d
`
`2a,b
`
`Vehicle: 1:1 Ora-Sweet: Ora-
`Plus.
`
`Amiodarone (86)
`
`1a
`
`2a,b
`
`Azathioprine (53)
`
`1a
`
`Baclofen (87)
`
`
`1a
`
`2d
`
`2d
`
`Vehicle: Simple syrup NF,
`methylcellulose, distilled
`water.
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`Ora-Plus; and cherry syrup.
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`
`3a (amber)
`
`3d (amber) 4a. 1 mg/mL mixture, with or
`without preservatives, stored
`in the dark was stable for 21
`days at 5 ºC and < 7 days at
`25 ºC. Mixtures prepared
`from pure powder are stable
`for 60 days at 25 ºC.
`4a. 3 mg/mL suspension was
`stable for 91 days at 4 and 25
`ºC; 21 mg/mL suspension
`was stable for 91 days at 25
`ºC.
`4a. 5 mg/mL mixture was
`stable for 91 days at 4 ºC and
`42 days at 25 ºC.
`3c (amber) 4a. 50 mg/mL mixture stored
`in the dark was stable for 60
`days at 5 and 25 ºC.
`3c (amber) 4a. 10 mg/mL mixture stored
`in the dark was stable for 60
`
`3a,b
`
`
`
`
`403
`
`Mylan Ex 1019, Page 6
`
`

`

`
`
`
`
`
`
`Table 1 continued
`Bethanechol
`chloride (88)
`
`Captopril (87)
`
`Chloroquine
`phosphate (83)
`
`Cisapride (83)
`
`1a
`
`1a
`
`1a
`
`1a
`
`Clonazepam (53)
`
`1a
`
`Clonidine
`hydrochloride (89)
`
`1a
`
`2d
`
`2d
`
`2d
`
`2d
`
`2d
`
`2d
`
`J Pharm Pharmaceut Sci (www. cspsCanada.org) 9 (3): 398-426, 2006
`
`Ora-Plus; and cherry syrup.
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`Ora-Plus; and cherry syrup.
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`Ora-Plus; and cherry syrup.
`
`days at 5 and 25 ºC.
`3c (amber) 4a. 5 mg/mL mixture stored
`in the dark was stable for 60
`days at 5 and 25 ºC.
`3c (amber) 4a. 0.75 mg/mL mixture
`stored in the dark in was
`stable for less than 10 days at
`5 and 25 ºC in the 1st two
`vehicles and only stable for 2
`days in cherry syrup under
`the same conditions.
`
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`Ora-Plus; and cherry syrup.
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`Ora-Plus; and cherry syrup.
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`Ora-Plus; and cherry syrup.
`
`3c (amber) 4a. 15 mg/mL mixture stored
`in the dark was stable for 60
`days at 5 and 25 ºC.
`3c (amber) 4a. 1 mg/mL mixture stored
`in the dark was stable for 60
`days at 5 and 25 ºC.
`4a. 0.1 mg/mL mixture stored
`in the dark was stable for 60
`days at 5 and 25 ºC.
`
`3c (amber)
`
`Vehicle: Purified Water USP,
`Simple Syrup NF.
`
`3a (amber) 4a. 0.1 mg/mL suspension
`stored in the dark was stable
`for 28 days at 4 ºC.
`
`Dantrolene (22)
`
`
`
`
`
`
`
`1b
`
`2d
`
`2 vehicles: consisting of citric
`acid monohydrate, water,
`syrup BP, with and without
`0.15% w/v methyl
`hydroxybenzoate.
`
`3d (amber) 4a. 5 mg/mL suspension, with
`or without preservatives,
`stored in the dark was stable
`for 150 days at 5, 25 and 40
`ºC.
`
`
`
`In aqueous solution
`captopril undergoes an
`oxygen-facilitated first-
`order oxidation by free
`radicals. Antioxidants
`(sodium ascorbate),
`decrease oxidation of
`captopril (44).
`Drug has a bitter taste.
`
`pH must be adjusted
`(sodium bicarbonate) to
`neutral.
`Clonazepam must be
`prepared as a suspension,
`since in solution it
`adsorbs to
`polypropylene/ PVC.
`Similar results were
`obtained from a solution
`prepared in the same
`vehicle with pure drug
`powder.
`The presence of excess
`citric acid in the
`formulation ensures
`dantrolene sodium is
`converted to the
`insoluble free acid.
`Suspension has a high
`
`404
`
`Mylan Ex 1019, Page 7
`
`

`

`Table 1 continued
`
`Dapsone (90)
`
`Diltiazem
`hydrochloride (87)
`
`1a
`
`1a
`
`Dipyridamole (87)
`
`1a
`
`Dolasetron
`mesylate (91)
`
`1a
`
`2a,b
`
`2d
`
`2d
`
`2d
`
`Domperidone (92)
`
`1a
`
`2a,b
`
`Enalapril maleate
`(83)
`
`Etoposide (93)
`
`Famotidine (94)
`
`Flecainide acetate
`(87)
`
`1a
`
`1d
`
`1a
`
`1a
`
`2d
`
`2a
`
`2e
`
`2d
`
`Fluconazole (95)
`
`1a
`
`2b,c
`
`
`
`
`
`
`
`Flucytosine (96)
`
`1b
`
`2d
`
`2 vehicles: 1:1 Ora-Plus:
`
`405
`
`J Pharm Pharmaceut Sci (www. cspsCanada.org) 9 (3): 398-426, 2006
`
`2 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; and simple syrup
`NF, citric acid, distilled water.
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`Ora-Plus; and cherry syrup.
`
`3c (amber) 4a. 2.0 mg/mL suspension
`was stable for 91 days at 4
`and 25 ºC.
`4a. 12 mg/mL mixture stored
`in the dark was stable for 60
`days at 5 and 25 ºC.
`
`3c (amber)
`
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`Ora-Plus; and cherry syrup.
`2 vehicles: 1:1 Ora-Plus:
`(8:1.5 Simple syrup NF:
`strawberry fountain syrup);
`and 1:1 Ora-Sweet SF: Ora-
`Plus.
`Vehicle: 1:1 Ora-Sweet: Ora-
`Plus.
`
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`Ora-Plus; and cherry syrup.
`Vehicle: 0.9% sodium
`chloride injection.
`Vehicle: Water for Irrigation
`USP, 1:1 Ora-Sweet: Ora-
`Plus. pH 5.8.
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`Ora-Plus; and cherry syrup.
`Vehicle: deionised water.
`
`3c (amber)
`
`4a. 10 mg/mL mixture stored
`in the dark was stable for 60
`days at 5 and 25 ºC.
`3b (amber) 4a. 10 mg/mL suspension was
`stable for 90 days at 3-5 ºC
`and 23-25 ºC.
`
`3b (amber)
`
`4a. 1 and 10 mg/mL
`suspensions were stable for
`91 days at 4 ºC and 25 ºC.
`3c (amber) 4a. 1 mg/mL mixture stored
`in the dark was stable for 60
`days at 5 and 25 ºC.
`10 mg/mL mixture was stable
`for 22 days at ~22 ºC.
`3c (amber) 4a. 8 mg/mL mixture stored
`was stable for 95 days at 23-
`25 ºC.
`3c (amber) 4a. 20 mg/mL mixture stored
`in the dark was stable for 60
`days at 5 and 25 ºC.
`1 mg/mL mixture stored in
`the dark was stable for 15
`days at 4, 23 and 45 ºC.
`3b (amber) 4a. 50 mg/mL suspension was
`
`3f
`
`3a
`
`viscosity when stored at
`5 ºC.
`Slight yellow colouration
`was observed from day
`28 at 25 ºC.
`Optimum pH ~5. Choice
`of sugars as excipients
`greatly influences drug
`stability (48).
`
`
`2nd vehicle is sugar-free
`and useful for patients on
`a ketogenic or diabetic
`diet.
`
`
`
`Optimum pH ~3.
`
`
`
`Stability is pH
`dependent.
`
`
`
`
`
`
`
`Mylan Ex 1019, Page 8
`
`

`

`
`
`
`
`
`
`J Pharm Pharmaceut Sci (www. cspsCanada.org) 9 (3): 398-426, 2006
`
`Table 1 continued
`
`Gabapentin (97)
`
`1b
`
`2a,b
`
`Ganciclovir (98)
`
`1b
`
`Granisetron (99)
`
`1a
`
`Hydralazine
`hydrochloride (83)
`
`1a
`
`2b
`
`2a
`
`2d
`
`Hydrocortisone
`(100)
`
`1a
`
`2a
`
`Isoniazid (101)
`
`1a
`
`2a
`
`(8:1.5 Simple syrup NF:
`strawberry fountain syrup);
`and 1:1 Ora-Sweet SF: Ora-
`Plus.
`2 vehicles: 1:1 Simple syrup
`NF: 1% methylcellulose; and
`1:1 Ora-Sweet: Ora-Plus.
`2 vehicles: Ora-Sweet; and
`Ora-Sweet SF.
`
`2 vehicles: 1:1 Simple syrup
`NF: 1% methylcellulose; and
`1:1 Ora-Sweet: Ora-Plus.
`3 vehicles: 1:1 Ora-Sweet:
`Ora-Plus; 1:1 Ora-Sweet SF:
`Ora-Plus; and cherry syrup.
`
`Vehicle: Polysorbate 80,
`sodium CMC, syrup BP,
`methyl- and propyl-
`hydroxybenzoate, citric acid
`monohydrate and water
`(Apparent pH ~3.4).
`
`Vehicle: Purified water BP,
`citric acid, sodium citrate,
`glycerol, compound
`hydroxybenzoate solution
`APF.
`
`Isradipine (102)
`
`
`1b
`
`2b,c
`
`Vehicle: Simple Syrup NF,
`Glycerin USP (wetting agent).
`
`stable for 90 days at 3-5 ºC
`and 23-25 ºC.
`
`3b (amber) 4a. 2.0 mg/mL suspension
`was stable for 91 days at 4 ºC
`and 56 days at 25 ºC.
`3c (amber) 4a. 100 mg/mL suspension
`was stable for 123 days at 23-
`25 ºC.
`3b (amber) 4a. 0.05 mg/mL suspension
`was stable for 91 days at 4
`and 25 ºC.
`3c (amber) 4a. 4 mg/mL mixture stored
`in the dark was stable at 5ºC
`for only 1 and 2 days in
`vehicles 1 and 2 respectively.
`No stability was observed for
`cherry syrup.
`3d (amber) 4a. 2.5 mg/mL suspension
`stored in