The preparation and stability of a liquid olanzapine preparation for oral administration in hospitals

AIM To assess the stability of a suspension of olanzapine in Guy’s hospital paediatric formula base for oral administration in hospitals.
DESIGN Analysis of suspensions by a high-performance liquid chromatographic method.
OUTCOME MEASURES Concentration of olanzapine in suspensions 0, 7, 14 and 21 days after preparation.
RESULTS Mean olanzapine concentration showed no major change over 21 days at 2–8C.
CONCLUSION A shelf-life of two weeks can be recommended for olanzapine suspension in Guy’s hospital paediatric formula base when it is stored in a refrigerator.

Olanzapine is an atypical antipsychotic agent used to treat schizophrenia and other psychiatric disorders.1 It is available as tablets (Zyprexa, Lilly) in 2.5mg, 5mg, 7.5mg or 10mg strengths. The usual dose is 5–20mg daily.2 However, some patients have difficulty in swallowing tablets and others find ways of not swallowing tablets even when supervised.

A liquid olanzapine preparation for oral use is not available commercially. We have found that Zyprexa tablets 10mg, crushed and suspended in Guy’s hospital “paediatric base”, provides a more palatable liquid oral olanzapine preparation than crushed tablets suspended in water.

In order to establish whether this suspension in paediatric base might be suitable for hospital use, we have assessed the stability of olanzapine in this medium at 2–8C in half-empty bottles over 21 days using high-performance liquid chromatography (HPLC).


High-performance liquid chromatography The HPLC method used was based on that developed for the measurement of clozapine in Guy’s hospital paediatric base.3 A 150 x 4.6mm internal diameter stainless steel column packed with Spherisorb S5 SCX (Phase Separations) was used with methanolic ammonium perchlorate (35mmol/L, pH 6.7) at a flow-rate of 1.5ml/min as eluent. Sample injection was performed using a Perkin-Elmer ISS-101 autosampler and detection was by UV absorption (260nm). Peak heights were recorded using a Hewlett-Packard 3392A integrator.
A methanolic stock solution of olanzapine pure compound (LY170053; Eli Lilly, Indianapolis, United States) (50mg olanzapine/50ml, ie, 1g/L) was prepared and stored at 2–8C. Portions of this solution were diluted in methanol:deionised water (93.5+6.5) to give calibration solutions containing 5mg, 10mg and 15mg olanzapine per litre. Portions (100µl) of each of the calibration standards were added to portions (100µl) of internal standard solution (10mg/L methanolic LY170222 [Eli Lilly])4 in autoinjector vials and vortex-mixed for 10 seconds. These solutions (20µl portions) were analysed in duplicate by HPLC as described above. The retention times of the internal standard and of olanzapine were approximately 10.0 min and 11.5 min, respectively. The olanzapine calibration solutions were freshly prepared by dilution from the stock solution on each analysis day.

Preparation of olanzapine suspension (1mg/ml) Zyprexa tablets (3 x 10mg) were halved and then crushed using a mortar and pestle and the powder suspended in 30ml Guy’s hospital formula base for paediatric mixtures (paediatric base), a syrup-based mixture containing carboxymethylcellulose BP, methylhydroxybenzoate BP and propylhydroxybenzoate BP.3 Each batch of olanzapine suspension was stored at 2–8C in a 50ml amber glass bottle in the dark.

Analysis of olanzapine suspension After inversion and vigorous shaking (1 min), 0.5ml of olanzapine suspension was added to 0.1mol/L aqueous hydrochloric acid (1ml) in a 50ml volumetric flask. After gentle mixing, the contents of the flask were allowed to stand (10 min) before diluting to the mark with methanol:deionised water (93.5+6.5). A portion (approximately 1ml) of the dilution was centrifuged (11,000 rpm, 4 min), and duplicate 100µl portions of the supernatant were added to internal standard solution (100µl) in autoinjector vials and vortex-mixed (10s). Portions (20µl) of these mixtures were then analysed by HPLC as described above. Analysis of a dilution of paediatric base (1+99) in methanol: deionised water (93.5+6.5) did not reveal the presence of interfering compounds.


The HPLC calibration standards were analysed on each analysis day and gave consistent results (mean gradient 0.0848, range 0.0754–0.0931, n=4). The plot of peak height of olanzapine:peak height of internal standard versus olanzapine concentration was linear (r=0.993 or better) and passed through the origin of the graph. Portions of olanzapine suspensions (n=3, freshly prepared on each day) were analysed by HPLC after dilution in duplicate with methanol:deionised water (93.5+6.5) on days 0, 7, 14 and 21. The results are given in Table 1. In each case the mean olanzapine concentration in the suspensions showed no major change over 21 days (range of mean concentrations [mg/ml] day 0, 0.96–1.04; day 21, 0.85–1.08). No additional peaks were present on the chromatograms on any day.


Olanzapine is very easily oxidised to olanzapine S-oxide in biological samples, the presence of an excess of ascorbate or some other redox reagent being required to ensure olanzapine stability during sample preparation and to convert any olanzapine S-oxide already present in the sample back to olanzapine.5 We, too, have found that ascorbate addition is needed to obtain reproducible results when using the HPLC system described above to measure plasma olanzapine concentrations in conjunction with solvent extraction.

The fact that no stability problems were apparent in the present study could be due to olanzapine stabilisation by one of the components of the paediatric base. In further experiments, addition of ascorbate to freshly prepared HPLC standards and to portions of olanzapine suspension which had been stored for 21 days at 2–8C did not result in an increase in the size of the olanzapine peak obtained on HPLC. A further possibility is that olanzapine S-oxide and olanzapine co-elute on the HPLC system used. We have been unable to obtain olanzapine S-oxide from a commercial source and experiments in which mild oxidation of olanzapine was attempted in vitro were inconclusive – treatment of olanzapine with 3 per cent (v/v) hydrogen peroxide under mildly acidic conditions had no apparent effect whereas use of 0.5 per cent (w/v) sodium nitrite, again under mildly acidic conditions, resulted in the appearance of three poorly retained compounds and the disappearance of the olanzapine peak. Even if S-oxide formation did occur in the suspension on standing, it is unlikely that this would affect olanzapine bioavailability per se as interconversion of the two compounds in vivo is probable.

Thus, the olanzapine suspensions studied showed no clear trend in olanzapine content over 21 days at 2–8C (Table 1). Each bottle was vigorously shaken and 0.5ml of suspension removed on each of four separate occasions. Differences in the distribution of tablet particles between the portions of suspension sampled could account for the differences between duplicates observed on some occasions. Possible explanations for the lower olanzapine recovery from suspension 3 (Table 1) include adsorption of olanzapine to the mortar and pestle or to the glass or cap of the bottle used to contain the suspension.

The suspension settled quickly and powdered tablet fragments formed a visible layer on the bottom of the glass bottle. Experience with the analogous clozapine suspension3 has shown that the need for vigorous shaking must be emphasised to nursing staff who may be asked to administer the suspension to patients. As with the clozapine suspension, informal assessment of the palatability of the olanzapine suspension has shown it to be well tolerated, some patients in fact preferring it to tablets. The suspension is useful in patients who have difficulty in swallowing tablets or who feign ingestion.
No tests of microbiological stability have been performed although paediatric base is preserved. It therefore seems prudent to recommend a shelf-life of two weeks when the product is stored in a refrigerator. Such a shelf-life is adequate for hospital use. We have no information on the bioavailability of olanzapine from the suspension, although it seems unlikely that olanzapine bioavailabilty will prove to be less than that from Zyprexa tablets.


We thank Mr B. Smith (pathology department, Maudsley hospital, London) for assistance and Eli Lilly for the gift of pure olanzapine and LY170222.

Ms Harvey is a clinical scientist at the medical toxicology unit of Guy’s and St Thomas’s hospital trust, where Dr Flanagan is consultant clinical scientist, and at the Maudsley hospital, London, where Mr Taylor is chief pharmacist. Correspondence to Mr Taylor at Pharmacy Department, Maudsley Hospital, Denmark Hill, London SE5 8AZ (e-mail


1. Fulton B, Goa KL. Olanzapine: a review of its pharmacological properties and therapeutic efficacy in the management of schizophrenia and related psychoses. Drugs 1997;53:281-98.
2. Nemeroff CB. Dosing the antipsychotic medication olanzapine. J Clin Psychiatr 1997;58(Suppl 10):45-9.
3. Ramuth S, Flanagan RJ, Taylor DM. A liquid clozapine preparation for oral administration in hospital. Pharm J 1996;257:190-1.
4. Catlow JT, Barton RD, Clemens M, Gillespie TA, Goodwin M, Swanson SP. Analysis of olanzapine in human plasma utilizing reversed-phase high-performance liquid chromatography with electrochemical detection. J Chromatogr B 1995;668:85-90.
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Last updated
The Pharmaceutical Journal, PJ, August 2000;()::DOI:10.1211/PJ.2024.1.222722

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