A stability-indicating HPLC procedure for determination of diltiazem hydrochloride in extemporaneously compounded oral liquids
A stability-indicating procedure for the determination of diltiazem hydrochloride in diltiazem hydrochloride (HCl) oral suspension and diltiazem HCl oral suspension, sugar free, is reported. Both suspensions were prepared from commercially available diltiazem HCl powder in a 1:1 (v/v) mixture of vehicle for oral solution and vehicle for oral suspension, and 1:1 (v/v) mixture of vehicle for oral solution, sugar free, and vehicle for oral suspension.
Table 3 Accuracy and precision results for diltiazem HCl in diltiazem HCl oral suspension (Formula 1) and diltiazem HCl oral
suspension, sugar free (Formula 2).
Specificity. To establish that there was no interference from other vehicle components or degradation products in the stability-indicating
ability of the procedure, individual optically active vehicle ingredients, both placebos and suspensions, were injected into
the HPLC. Figures 1 and 2 depict typical chromatograms of the assay preparations of diltiazem HCl oral suspension and diltiazem
HCl oral suspension, sugar free, respectively. The diltiazem peak was well resolved from the vehicle ingredients and the main
degradation product, desacetyl diltiazem.
To further evaluate the specificity of the procedure forced degradation studies were performed. For photochemical and thermal
degradation studies, a 5 mL aliquot of each suspension and placebo was subjected to short-wave and long-wave ultraviolet and
visible light and to 90 °C for 24 h. Acid-, base- and oxidizer-treated samples were prepared by mixing a 5 mL aliquot of each
suspension and placebo with 5 mL of 0.1 N hydrochloric acid, 0.1 N sodium hydroxide and 3% hydrogen peroxide and letting them
sit at ambient temperature for 24 h (Formula 1 was exposed only to base for 1 h). After degradation treatment, samples were
allowed to cool to room temperature, if necessary. Acid- and base-treated samples were neutralized with an appropriate amount
of 0.1 N sodium hydroxide and 0.1 N hydrochloric acid, respectively. All samples were prepared and analysed using the sample
preparation procedure and the chromatographic conditions described in the experimental section. Diode array detection was
employed for spectral purity analysis of the diltiazem peak in the stress samples over a range of 200–700 nm. The diltiazem
peak was considered spectrally pure when the peak purity value was greater than 0.996. The area responses of diltiazem HCl
in the stress samples were compared to those in the untreated samples and reported as percent diltiazem HCl concentration
remaining. The results of the forced degradation study for both suspensions, including the peak purity values obtained by
using the capability of the chromatographic software ChemStation, are shown in Tables 1 and 2.
Both suspensions significantly degraded under all stress conditions except UV and visible light exposure. The greatest number
of additional peaks, 10, was produced when an aliquot of either suspension was stressed with hydrogen peroxide solution. A
typical chromatogram of a hydrogen peroxide–stressed suspension sample is shown in Figure 3. None of the detected additional
peaks displayed retention times that overlapped the diltiazem peak under any stress condition. All of the diltiazem peaks
had a peak purity value greater than 0.996 except Formula 1, which under basic stress conditions for ~1 h yielded a diltiazem
peak purity of 0.9792. Adjustments in the HPLC conditions did not improve the diltiazem peak purity in the base-stressed sample.
Also, there was no significant degradant peak observed at the retention time of diltiazem in the stressed placebos. Despite
various stresses and degradation conditions the diltiazem peaks demonstrated spectral purity, which supports the use of this
procedure to monitor the stability of diltiazem HCl oral suspension and diltiazem HCl oral suspension, sugar free.
Linearity. The range of the assay procedure was set at 70–130% of the diltiazem HCl label claim in the suspensions. Linearity of the
detector response was investigated at five levels from 70% to 130% (set 1) and at seven levels covering a wider range from
0.1% to 200% (set 2) of the nominal assay sample concentration. A single injection of each of the linearity solutions was
made and plots of peak area versus concentration were constructed. Linear regression was performed and the correlation coefficients
were calculated. The correlation coefficients were 0.9995 (set 1) and 1.0000 (set 2) (desired correlation coefficient: ≥0.999).
The percentage of the intercept relative to 100% analyte was in the range ±2% which is considered negligible.7,8 The range of the procedure was determined to be 0.0012–2.41 μg/mL (0.1%–200% of the nominal sample concentration of 1.2
mg/mL). Further ranges may be applicable but were not investigated.