Chlorpromazine

Abstract

The stability of perphenazine in oral liquid dosage forms was studied by means of a stability-indicating high-performance liquid chromatography assay method that was developed in our laboratory. There was a direct relationship between the peak heights and the concentrations, with an r value of 0.998. The percent relative standard deviation based on five injections was 0.6. The products of decomposition and excipients present in the dosage forms did not interfere with the developed assay method. The dosage forms were stable for only 30 days when stored in amber-colored glass bottles at room temperature. The pH value of the mixtures remained constant at 3.7 after 90 days of storage, and the physical appearance of the mixtures did not change. The beyond-use date of 30 days is recommended for this product.

Introduction

Perphenazine is a phenothiazine derivative similar to chlorpromazine (Figure 1). It exerts moderate anticholinergic and sedative effects, and also strong extrapyramidal and antiemetic activities. A formula for compounding an oral liquid dosage form of perphenazine has been reported.1 As no stability studies had been reported for this formulation, the default beyond-use date assigned was 180 days based on the guidelines reported in the United States Pharmacopeia-National Formulaiy (USP-NF).2

The purposes of this investigation were (1) to develop a stability-indicating high-performance liquid chromatographic (HPLC) assay method for the quantitation of perphenazine, and (2) to study the stability of perphenazine in oral liquid dosage forms.

Materials and Methods

Chemicals and Reagents

All the chemicals and reagents were USP-NF or American Chemical Society (ACS) grade and were used without further purification. Perphenazine powder (Lot 74509) was generously supplied by Professional Compounding Centers of America, Houston, Texas.

Equipment

An HPLC system (ALC 202 pump and model 484 multiple wavelength detector; Waters Corporation, Milford, Massachusetts) equipped with an injector (Model 7125; Rheodyne, Cotati, California) and a recorder (Omniscribe 5213-12; Houston Instruments, Austin, Texas) were used. The column used (microCN, 15 cm, 4.6 mm ID, 5 µm) is available from Waters Corporation. All pH values were measured using a Beckman SS-3 Zeromatic pH meter (Beckman Instruments, Fullerton, California).

Chromatographic Conditions

The mobile phase contained 50% (v/v) acetonitrile in water containing 1% of glacial acetic acid and enough 85% phosphoric acid to set the pH at 2.6. The flow rate was 1.2 mL/minute, the sensitivity was 0.9 AUFS at 257 nm, the chart speed was 30.5 cm/hour, and the temperature was ambient.

Preparation of Oral Liquid Dosage Forms of Perphenazine

The oral liquid dosage forms (0.5 mg/mL) were prepared according to a previously published formulation,1 except that anhydrous citric acid (50 mg per 50 mg of the drug) was used to assist in dissolution of the perphenazine instead of 5 mL of glycerin. Dissolving the drug in glycerin was extremely difficult; moreover, citric acid is a component of Ora-Sweet, the vehicle recommended.1 For both of the preparations, Ora-Sweet was used as the vehicle. One of the dosage forms contained 0.1% sodium metabisulfite as an antioxidant, and the other did not contain any antioxidant. The initial pH value of both formulations was 3.7. The ingredients were (per 100 mL) perphenazine 50 mg; water 5 mL; citric acid anhydrous 50 mg; and Ora-Sweet (Lot 3H6754, Paddock Laboratories, Minneapolis, Minnesota) qs to 100 mL. Although the pH of Ora-Sweet has been reported to be approximately 4.2, the lot of Ora-Sweet we used for the study, which had been stored in our lab (no expiration date was indicated on the product's label), had a pH value of 3.5. Even the pH value of 4.2(1) is not within the range (4.5 to 4.9) of a commercially available oral concentrate solution.1 Before bringing to volume with Ora-Sweet, 50 mg of the drug was dissolved in 5 mL of water containing 50 mg of citric acid. After the initial data (assays, pH values, and physical appearance), the dosage forms were stored at room temperature (25°C) in 240-mL amber-colored glass bottles (Owens-Illinois, Toledo, Ohio). Data were collected at the appropriate intervals.

Preparation of Standard Solutions

The stock solution of perphenazine (0.5 mg/mL) in water containing 50 mg of citric acid was prepared fresh daily using a simple solution method. The stock solution was used to prepare solutions of lower concentrations as needed by diluting with water. The most commonly used standard solution contained 50 µg/mL of perphenazine.

Preparation of Assay Solutions

A 5.0-mL quantity of the assay mixture was diluted to 50 mL with water.

Decomposition of Perphenazine

A 25-mL quantity or the standard solution (50 µg/mL) was transferred to a 150-mL beaker and heated to boiling on a hot plate. More water was added to the solution as needed. After 45 minutes, the solution was allowed to cool, the volume was brought to 25 mL with water, and the solution was injected into the chromatograph using the following procedure. The results are presented in Table 1.

Assay Procedure and Calculations

An 80-µL quantity of assay solution was injected into the chromatograph under the described conditions. Since there was a direct relationship between the peak heights and the concentrations (range tested, 25 to 55 µg/mL with an r value of 0.998), the results were calculated using a standard curve (Figure 2). The results are presented in Table 1.

Results and Discussion

Assay Methods

The developed HPLC assay method is stability indicating, since the product of decomposition did not interfere with the assay procedure (Figure 3). Furthermore, the inactive ingredients presented in the dosage form (i.e., citric acid, sucrose, glycerin, sorbitol, sodium phosphate, flavor, methylparaben, sodium benzoate) did not interfere with the assay procedure. The standard solution, which was decomposed using heat, lost approximately 48% of its potency (Table 1). There was a direct relationship between the peak heights and the concentration of the drug (range tested, 25 to 55 µg/mL). The developed method is accurate and precise with a percent relative standard deviation based on five injections of 0.6 and an r value for the standard curve of 0.998.

The assay results indicate that perphenazine was stable for only 30 days in both of the oral liquid dosage forms when stored in amber-colored glass bottles at room temperature (Table 1). The pH value of 3.7 for both the formulations remained constant, and the physical appearance did not change after 90 days of storage. The previously recommended default beyond-use date of 180 days1,2 is not appropriate for perphenazine in this vehicle. The percent of intact drug remaining after 62 days was 87.8% in the solution with an added antioxidant (sodium metabisulfite) and 83.3% in the solution without an antioxidant. Thus the antioxidant offered only a marginal improvement. It is well known that the phenothiazine derivatives are subject to oxidation,3 and the oxidation is catalyzed by light. In this investigation, the pH value of the dosage forms was 3.7, while the predicted value was 4.2.1 This deviation from predicted pH may have affected the stability of perphenazine. Even the pH value of 4.2 is not within the pH range (4.5 to 4.9) of the commercially available oral concentrate solution.1

The decomposition of perphenazine followed first-order law (Figure 4), and the product of decomposition (peak 2 in Figure 3) was from perphenazine sulfoxide.4 The author is presently investigating the stability of new dosage forms of perphenazine in (1) a current lot of Ora-Sweet at a pH value of 4.2, and (2) a different commercially available syrup with a pH value of 4.5; these results will be reported later. Preliminary findings indicate that the results at pH 4.5 are encouraging, while those in the recommended Ora-sweet vehicle (pH 4.2) are not.1

References

1. Allen LV Jr. Perphenazine 2.5-mg/5-mL syrup. IJPC 2003; 7(6): 473.

2. US Pharmacopeial Convention, Inc. United States Pharmacopeia 26-National Formulary 21. Rockville, MD: US Pharmacopeial Convention, Inc.; 2002:2197-2201, 2574.

3. Ravin LJ, Kennon L, Swintosky JV. A note on the photosensitivity of phenothiazine derivatives. J Am Pharm Assoc (Baltim) 1958; 47(10): 760.

4. Beaulieu N, Lovering EG. Liquid chromatographic method for perphenazine and its sulfoxide in pharmaceutical dosage forms for determination of stability. J Assoc Off Anal Chem 1986; 69(1): 167-169.

Vishnu D. Gupta, PhD

Pharmaceutics Division

University of Houston

Houston, Texas

Address correspondence to Vishnu D. Gupta, PhD, Pharmaceutics Division, University of Houston, 1441 Moursund Street, Houston, TX 77030. E-mail: vgupta@uh.edu

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