Formulation in Pharmacy Practice eMixt updates

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This page contains information on new formulations, information not included in eMixt, monograph revisions and updates. The content will be driven by a regular review of the literature, and your questions or comments. If you have any comments or suggestions please send these by e-mail
Please note, it is recommended that you consult the cited references for further information.
Updates are added to this page regularly. The most recent additions are highlighted below. Click on the links or scroll the page to view the whole archive.

28/04/02
Vigabatrin
Vigabatrin sachets are not available in all countries and paediatric doses must be prepared by other means. Vigabatrin dissolves in water but is chemically unstable in solution. Preparation of an oral liquid from tablets is not recommended due to lack of stability information.

Recommendations:

1. Immediately prior to administration, dissolve the tablet in a known volume of water and measure out the required dose with an oral syringe.Discard any remaining solution.

2. Crush tablets and pack fractional doses into powder papers or gelatin capsules. Add the powder to liquid prior to administration. Protect the doses from moisture and use within 30 days of preparation.

Posted by David Woods [Comments or Feedback]

28/04/02
Methadone
Liquids are commercially available in most countries but there have been occasional requests for information on extemporaneous formulation. Please email any comments or additional suggestions.

This is reported to be chemically stable for at least 4 months at room temperature.
Reference:Ching MS et al. Stability of methadone mixture with methylhydroxybenzoate as a preservative. Aust J Hosp Pharmacy 1989;19(3):159-161

Alternatives
Based on the above methadone should be stable for at least 30 days in a vehicle containing syrup and or glycerol (flavored if necessary) preserved with parabens. Addition of 1% citric acid is also recommended.
Lauriault et al determined that methadone was stable in a variety of acidic flavours (eg Tang, apple juice) for up to 30 days.
Lauriault G, LeBelle MJ, Lodge BA, Savard C. Stability of methadone in four vehicles for oral administration.Am J Hosp Pharm 1991 Jun;48(6):1252-6 PubMed

28/04/02
Mefloquine
There have been several questions about this but I have not located any stability studies.
The drug (mefloquine HCL) is a white to almost white crystalline compound, slightly soluble in water. Slightly soluble is 1 - 10 mg per mL, so a 20 mg in 5 mL liquid would probably be a mixed suspension/solution.
As the dose is either stat or once weekly a tablet fraction (eg quarter or a half) crushed and mixed with a palatable liquid is the most appropriate way of giving the dose. Preparation of an oral liquid for multiple doses cannot be justified due to lack of stability information.

Posted by David Woods [Comments or Feedback]

29/01/02
Domperidone oral liquid
Domperidone suspensions of both 1 and 10 mg/mL in a 1:1 mixture of Ora-Sweet and Ora-Plus were reported to be physically and chemically stable for a period of up to 91 days, both at room temperature and under refrigeration. An expiration date of 91 days was suggested. The pH of the suspensions ranged from about 4.3 - 4.6.
Reference
Ensom, Mary H.H., Decarie, Diane., Hamilton, Don P. Stability of Domperidone in Extemporaneously Compounded Suspensions. Journal of Informed Pharmacotherapy 2002;8 (Jan-Mar) [Full Text]

NB
Ora-Sweet and Ora-Plus are not available in most countries outside USA and Canada. The formula suggested in the eMixt monograph (prior to publication of this study) is a possible alternative as the ingredients are similar to the components of Ora-Plus. Add citric acid to ensure the pH is in the range quoted above and assign a more conservative expiration date (30 days suggested).

Posted by David Woods [Comments or Feedback]

31/12/01
Compatibility of drugs in syringe drivers
Palliativedrugs.com has two charts of compatibilities, one for two drug mixtures and another for three drug mixtures. You may have to log-in and register to access these sites. The charts provide useful information on the compatibility of many drug combinations but unfortunately there is no information on morphine mixtures as diamorphine is used in the UK.

Pallmed.net contains a searchable database of drug compatibilities in syringe drivers, compiled by Dr Ian Back. Reports are given an evidence weighting and the primary references are cited if appropriate. The database can also be downloaded as a pdf file.

22/11/01
Ganciclovir
Anaiazi et al have reported the stability of ganciclovir liquid compounded from capsules in base of Ora- Sweet or Ora-Sweet SF . A 100 mg/mL oral liquid is stable for 120 days at 23-25 C in these bases. The final pH was 4.5. Microbial testing was not performed and a shorter expiry date (eg 30 days) is more appropriate.
Anaizi et al Am J Health-Syst Pharm 1999;56(17)1738-41 [PubMed link]

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21/11/01
Dexamethasone Liquid
The stability of dexamethasone sodium phosphate (as injection) diluted in Ora-Plus/Ora-Sweet has been reported by Wen-Lin Chou et al Click here for full text pdf (Adobe Acrobat file)
Can J Hosp Pharm 2001:54:96-101

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20/11/01
What is "triple bromide" mixture, used for the treatment of intractable seizures ?

Bromides have been used to treat epilepsy for over 100 years. They are still used occasionally in severe cases, especially in children with underlying brain damage. Bromides have traditionally been given in a solution consisting of sodium, potassium and ammonium salts of bromide in equal amounts (by weight) of each. The usual preparation contains 1200 mg (400 mg of each salt) in 5 mL.
The base can be a syrup and water mix. A one month expiry date and refrigeration is suggested.

Recommended doses: children less than 6 years: 300 mg BD to 600 mg TID
children 6 years and older: 300 mg to 1000 mg TID
The half-life of bromide is about 12 days therefore steady state is not reached for about one month. Toxicity (bromism) can occur and plasma concentrations of bromide should be monitored. Increased sodium intake increases bromide clearance and vice-versa.
Nahata and Hipple (Pediatric Drug Formulations 4 th edition) describe Three Bromides Mixture prepared in a base of Ora-Plus. They suggest that this is stable for 12 months but state that this is based on experience rather than stability testing.

References
Levy R et al (eds) Antiepileptic Drugs, 3rd Ed. Raven Press, New York, 1989.
Martindale 31st Edition.

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12/10/01
Hydrochlorothiazide

Hydrochlorothiazide is very slightly soluble in water and soluble in alcohol. Aqueous solubility is reported to be 0.6 - 1 mg/mL (1)
Hydrochlorothiazide 5 mg/mL and spironolactone 5 mg/mL prepared from tablets in a 1:1 mixture of Ora-Sweet and Ora-Plus, or a 1:1 mixture of Ora-Sweet SF and Ora-Plus or Cherry Syrup was stable for up to 60 days at 5°C or 25°C, protected from light.2 The final pH of this preparation was 4.2 - 4.4

If hydrochlorothiazide suspension (without spironolactone) is required use the same formula as above. If these bases are not available, the following formula is suggested:-

* If possible check the final pH is less than 5
Expiry date: 30 days. Refrigerate, protect from light.

References:
1. Deppeler HP. Hydrochlorothiazide. In: Florey K, ed. Analytical profiles of drug subtances. Vol 17. New York: Academic Press;1981:405-41
2. Allen L.V., Erickson M.A. Stability of labetalol hydrochloride, metoprolol tartrate, verapamil hydrochloride and spironolactone with hydrochlorothiazide in extemporaneously compounded oral liquids.Am J Health-Syst Pharm 1996; 53: 2304-9. [PubMed link]

Posted by David Woods [Comments or Feedback]

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26/09/01
Lansoprazole
A single-dose crossover study in 36 healthy volunteers compared the pharmacokinetics and effect on intragastric pH of lansoprazole suspension with that of intact capsules. The simplified lansoprazole suspension (prepared as per the eMixt monograph) was shown to be bioequivalent to the intact capsule and to effectively control intragastric pH.
Thao T.Doan et al.Comparative pharmacokinetics and pharmacodynamics of lansoprazole oral capsules and suspension in healthy subjects. Am J Health-Syst Pharm 2001;58(16):1512-19.
[ PubMed link]

09/07/01
Pantoprazole
Pharmacia have recently issued information about the preparation of a suspension for NG tube administration referring to a study by Ley et al (Gastroenterology 2001, in press). A suspension was prepared using a 40 mg pantoprazole tablet buffered with 260 mL of 1.4 % sodium bicarbonate. Total bioavailability was 93 % compared with the intact tablet. Cmax was about 10 % higher due to faster absorption. Please contact your local Pharmacia office for more information.
Posted by David Woods [Comments or Feedback]

22/06/01
Baclofen
I have had some feedback that Formula A in eMixt is excessively thick, especially when refrigerated This formula was based on a published study and the problem was not identified. However, syrup will often thicken and crystallize when exposed to fluctuating temperatures. Formula A should also be stable at RT if adequately preserved. Formula B or C are alternatives.
Baclofen is a demo file so click here to view if you don't have a copy of the CD.

06/06/01
Omeprazole
A recent study has compared the pharmacokinetics of omeprazole capsules with SOS (simplified omeprazole suspension). Subjects were given a daily 20 mg dose of omeprazole as either the capsule or 20 mg in 10 mL suspension. After 7 days of treatment the AUC for SOS was 49% lower than that of the capsule. The authors suggested that SOS may need to be given more frequently than once daily to maintain adequate acid suppression. The subjects did not receive the loading dose that is normally recommended when initiating SOS.
Further studies are required to determine the optimum dosing regimen for SOS.

Reference.
Song JC, Quercia RA, Fan C, Tsikouris J, White CM. Pharmacokinetic comparison of omeprazole capsules and a simplified omeprazole suspension. Am J Health Syst Pharm 2001 ;58(8):689-94 [PubMed Link]

Note: The links from the eMixt monographs for omeprazole and lansoprazole are no longer active. I am trying to trace new links.

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28/05/01
Boric Acid Pessaries
Boric acid pessaries have been evaluated for the treatment of resistant vulvovaginal candidiasis especially infections due to C.glabrata. Although vaginal suppositories have been formulated a frequently used alternative is to pack the dose (600 mg of boric acid) into a size 0 gelatin capsule. The usual dosage is one capsule inserted daily for 14 days. This preparation is reported to be well tolerated and there is some evidence to show that this is an effective treatment when indicated. Boric acid pessaries should not be administered to pregnant women. Please refer to the literature for more information on effectiveness and safety. [PubMed Link]

28/05/01
Hyoscine butylbromide Oral liquid
Oral liquids (e.g. Buscopan) are available in some countries. Hyoscine butylbromide is freely soluble in water and the injection has a pH of about 5.5. Relevant stability studies have not been located.
The injection could be given orally and if necessary diluted with Water for Injection to give an easily measurable dose volume. Alternatively an oral liquid can be prepared by adding the injection or crushed tablets to a base of 40% syrup or glycerol in water with the addition of parabens 0.1 % as an antimicrobial preservative. A conservative expiry date of 14 days is suggested due to lack of confirmed stability data. Commercially available diluents such as Ora-Plus and Roxane diluent should also be suitable.
Formula suggested by David Woods [Comments or Feedback]

15/05/01
Norfloxacin
An extemporaneously prepared suspension of norfloxacin 20 mg/mL was stable for at least 56 days when stored at room temperature or under refigeration. Commercially available Noroxin® tablets and a vehicle of equal parts Ora-Plus® and strawberry syrup were used. Ora-Plus® is not available in some countries. The tablet dispersion method described in the eMixt monograph remains an alternative method.
Reference:
Johnson CE, Price J, Hession JM. Stability of Norfloxacin in an extemporaneously prepared oral liquid. Am J Health-Syst Pharm 2001; 58(7):577-79 [Comments or Feedback]

03/05/01 and 28/04/02
Levodopa/Carbidopa
Levodopa/carbidopa solution, with the addition of Ascorbic Acid, has been used to control severe fluctuations in patients with Parkinson's Disease. The preparation is also known as LCAS. Patients drink the solution and can titrate the dose to effect. The addition of ascorbic acid improves stability such that solutions can be prepared on a daily basis by the patient or caregiver.
The method described by Kurth et al is as follows:-
Mix 10 tablets of either carbidopa 10 mg/levodopa 100 mg, or carbidopa 25 mg/levodopa 100 mg (equivalent to 1000 mg levodopa), 2 g of ascorbic acid, and 1000 mL of water.
Rotate or shake the container gently until the tablets dissolve. Crushing the tablets is not usually necessary as they disperse easily.
The final concentration will be carbidopa 0.1 mg/mL-levodopa 1 mg/mL or carbidopa 0.25 mg/mL-levodopa 1 mg/mL and ascorbic acid 2 mg /mL
The solution is stable for 24-48 hours if refrigerated.

Reference:
Kurth MC, Tetrud JW, Irwin I, Lyness WH, Langston JW.
Oral levodopa/carbidopa solution versus tablets in Parkinson's patients with severe fluctuations: a pilot study. Neurology 1993 May;43(5):1036-9 [PubMed] [Related PubMed citations]

28/04/02
Levodopa/carbidopa is also stable in Ora-Plus/Ora-Sweet
Nahata MC, Morosco RS, Leguire LE.
Development of two stable oral suspensions of levodopa-carbidopa for children with amblyopia
J Pediatr Ophthalmol Strabismus 2000 Nov-Dec;37(6):333-7 PubMed

Posted by David Woods [Comments or Feedback]

01/05/01
Levofloxacin
VandenBussche HL, Johnson CE, Fontana EM, Meram JM. Stability of levofloxacin in an extemporaneously compounded oral liquid. Am J Health Syst Pharm 1999;56(22):2316-8
[PubMed Link] [Comments or Feedback]

20/04/01
Sodium Butyrate
Sodium butyrate enemas appear to be beneficial in acute radiation proctitis. In this study, 20 patients with ARP received sodium butyrate 80 mmol/L as a daily 80 mL enema or sodium chloride (placebo) for 3 weeks in a crossover design. A significant improvement in ARP symptom scores was observed with sodium butyrate but not with sodium chloride over the three week treatment period. When the initial placebo recipients were switched to sodium butyrate, 8/9 evaluable patients experienced clinical remission. Three patients initially treated with sodium butyrate relapsed after switching to placebo. No production or stabilty details were provide in the publication.

Reference
Vernia P, Fracasso PL, Casale V, Villotti G, Marcheggiano A, et al. Topical butyrate for acute radiation proctitis: randomised, crossover trial. Lancet 356: 1232-1235, 7 Oct 2000
[Comments or Feedback]

18/04/01
Hydroxychloroquine
An oral liquid made from hydroxychloroquine will have an extremely bitter taste. No formal stability studies have been located. If you are using the sulphate salt this is freely soluble in water so there is no real need for a suspending agent such as methylcellulose. A base of 40 % glycerol (sweet but no tooth decay) and water with 0.1 % parabens could be used. Then I suggest that this simple mixture is added to the child's favorite drink immediately prior to administration. A range of flavours could be tried in an attempt to make the mixture palatable. This simple mixture (ie without the flavour) should be stable for 30 days if protected from light and refrigerated.
Formula suggested by David Woods [Comments or Feedback]
There is also a formula in "Trissel's Stability of Compounded Formulations" from an article by Pesko in Am Druggist 1993:207:57. A 50:50 mixture of Ora-Plus and water was used for the base and a 30 day expiry date suggested in the absence of stability testing.