Dapsone

Abstract

The qualification and quantification of dapsone in suspension were developed and shown to be stability indicating by means of a reverse-phase high-performance liquid chromatographic method. The real solubility of dapsone in water was calculated to be 0.208 mg/mL at 25 deg C. The enthalpy of solution and the entropy of solution were calculated to be -175.6 J/g and -43605.7 J/K/M, respectively. An extemporaneous suspension was formulated from commercially available dapsone tablets, and the chemical stability of dapsone in the suspension was determined by means of accelerated stability testing. The 91-day analytical stability testing study was conducted at 4, 30, 50, 60, and 70 deg C. The energy of activation for the suspension was determined to be -23288.35 J/K/M. The zero-order rate of degradation for dapsone (k^sub 0,25^) in suspension at 25 deg C was found to be 0.040845 day^sup -1^. The first-order rate of degradation for dapsone in solution was found to be 0.196370 (mg/mL)(day^sup -1^). The shelf life for the suspension was calculated to be 31.67 days at 25 deg C and 230.76 days under refrigeration at 4 deg C.

Introduction

Extemporaneous formulations play an important role in treating pediatric patients. Many frequently used drugs are not available in a suitable dosage form for these patients and cannot be used for patients who are unable to swallow tablets or capsules.1 Pharmacists usually extemporaneously compound these dosages. However, stability data are often lacking for these products.1 This issue raises a problem for the pharmacist because a beyond-use date must be set for these preparations. Many times the beyond-use date is set by the pharmacist on the basis of USP guidelines and/or professional communication with the manufacturer.1 This study was conducted using dapsone, which pharmacologically is both bactericidal as well as bacteriostatic against Mycobacterium leprae.2

Pneumocystis carnii pneumonia (PCP) is the most common opportunistic infection in patients with acquired immunodeficiency syndrome. Preliminary reports suggest that a daily dose of 50 to 100 mg of dapsone is effective for the primary or secondary prophylaxis of pneumonia in acquired immunodeficiency syndrome patients. Dapsone is commonly used as an alternative prophylactic agent for children intolerant to trimethoprim-sulfamethoxazole.3 Dapsone has been proven to be a safe and effective alternative to trimethoprimsulfamethoxazole or pentamidine as a prophylactic for PCP in HIV-positive patients. Recently, it has been proposed that dapsone might be used in combination with pyrimethamine for the prophylaxis of both PCP and cerebral toxoplasmosis.4 In order to reduce a secondary dapsone resistance, the therapy needs to be maintained at full dosage (100 mg/day) without interruption, combined with one or more antileprosy drugs as recommended by the World Health Organization Expert Committee on Leprosy and the US Public Health Service.5 Dapsone is available as 25- and 100-mg tablets for oral administration.

A stability-indicating reverse-phase high-performance liquid chromatographic (HPLC) assay method was developed for the study and was used for the analysis of dapsone in solution. The USP suggests a normal-phase HPLC assay method for the analysis of dapsone that involves a triple-component mobile phase.6 Gordon and Peters7 separated dapsone, monoacetyl dapsone, and diacetyl dapsone at a level of 1 to 20 mg on a silica-gel column with ethyl acetate as the solvent.

An extemporaneous suspension using commercially available dapsone tablets was prepared, and the physical and chemical stability of the suspension was determined. The shelf life for the extemporaneous preparation was calculated using accelerated stability testing. Nahata and Hipple1 described the extemporaneous formulation of a 2-mg/mL oral suspension with a stability period of 21 days, on the basis of a professional communication with Jacobus Laboratories. Nahata and Morosco8 determined the stability of dapsone in Ora Plus:Ora Sweet, as well as in simple syrup, citric acid, and water. Dapsone was stable for 91 days in both formulations when stored at 4 deg C and at 25 deg C. The objectives of our study were to formulate an oral liquid suspension for dapsone from commercially available dapsone tablets by means of a procedure simple enough to allow the suspension to be reproduced extemporaneously in a community or hospital pharmacy, and to investigate the chemical stability of dapsone in the formulation

using accelerated stability testing to arrive at the shelf life for the product.

Materials and Experimental Methods

Reagents and Chemicals

Acetonitrile, HPLC grade, 99.9% pure, ultraviolet cut-ff 190 nm, Lot 994706, was obtained from Fisher Scientific (Fairlawn, New Jersey). Dapsone 97% pure, 4,4(1)-Aminophenyl sulfone, Lot 04702TS, was obtained from Aldrich Chemical Company, Inc. (Milwaukee, Wisconsin). Caffeine USP Anhydrous, Lot C710463, was obtained from Amend Drug & Chemical Company, Inc. (Irvington, New Jersey). Sodium Hydroxide, 98.1% pure, certified ACS, Lot 893102, was obtained from Fisher Scientific. Fisher Scientific also supplied the HCL 38.0% w/w, ACS grade, Lot 920005.

HPLC Instrumentation and Conditions

The HPLC system consisted of two Waters 501 HPLC pumps with a 2200-(mu)L loop injector (Waters Corporation, Milford, Massachusetts). The detector used was a Waters 486 tunable ultraviolet detector (Waters Corporation). The sample processor was the Waters 712 WISP (Waters Intelligent Sample Processor, Waters Corporation). The software for acquiring and processing the data was the Version 2.1 Millennium (Waters Corporation). The column was a Nova-pak, C^sub 18^, 3.9 x 150 mm with a particle size of 5 (mu)m, (Waters Corporation). The flow rate of the mobile phase was programmed to be 1.0 mL/minute. The detector was set at 274 nm. The column was maintained at room temperature throughout the analytical procedure. The mobile phase was prepared and filtered through a 0.45-(mu)m FP vericel Membrane Filter, HPLC certified, Lot 2092010 (Gelman Sciences, Ann Arbor, Michigan), with the help of a Millipore Filter Holder, part 4, which was obtained from Millipore Filter Corporation (Bedford, Massachusetts). A (40:60) acetonitrile in water solution was used as the mobile phase and was run with a flow rate of 1.0 mL/minute. The complete run was performed within 4 minutes, which also included a 1-minute wash time. The sample processor was adjusted to inject 10 (mu)L of the sample into the column.

Preparation of the Dapsone Suspension

To prepare the suspension (see Table 1), we crushed and triturated 450 tablets of 100-mg Dapsone USP (Lot 10393, courtesy of David P. Jacobus, MD, Jacobus Pharmaceutical Company, Inc., Princeton, New Jersey) using a mortar and pestle. Carboxymethylcellulose sodium, viscosity 7MF (Lot W42042404, Amend Drug & Chemical Company, Inc., conforming to USP or FCC specifications), and Veegum HV, colloidal magnesium aluminum silicate (Lot 224190, Vanderbilt Chemical Corporation, Norwalk, Connecticut) were individually hydrated in distilled water overnight. Orange Oil USP (Lot CX128845, Lorann Oils, Inc., Lansing, Michigan) was added, with constant trituration, to the tablet powder. The hydrated carboxymethylcellulose was slowly added to the tablet powder with constant trituration. The hydrated Veegum and Sorbitol Solution USP (Lot Y48134M16, Ruger Chemical Company, Inc., Irvington, New Jersey) were added individually with constant trituration. The contents of the mortar were then transferred to a 4000-mL beaker. An electric laboratory stirrer (Phipps & Bird, Inc., Richmond, Virginia) and an electric laboratory mixer (Palo Laboratory Supplies, Inc., New York, New York) were used to disperse and mix the suspension. Paraben concentrate (methylparaben 10%, propylparaben 2%, propylene glycol as needed to 1000 mL) (Lot 1117ASK, The University of Toledo, Toledo, Ohio) was added to the beaker, and the stirrer remained in operation until the suspension was properly mixed. This suspension was stored in a refrigerator at 4 to 6 deg C.

Stability Study for the Dapsone Suspension

The dapsone suspension was prepared and stored in the refrigerator at 4 to 6 deg C in an amber-colored bottle, to minimize the degradation of the dapsone. The stability study utilized 240-mL amber-colored type NP glass bottles. A 200-mL portion of the suspension was placed into three amber-colored bottles. A temperature close to room temperature was chosen as the initial investigative temperature (30 deg C), and the suspension was analyzed for dapsone for 15 days at this temperature. On a weekly basis, the refrigerated suspension was analyzed for dapsone; and the loss of dapsone was calculated to obtain a baseline and establish stability. At the end of the 15-day period, the next temperature chosen for study was 70 deg C. The decision as to a 70 deg C study temperature was based on the results obtained from a study period of 30 days at 30 deg C and 15 days at 60 deg C. The fourth temperature chosen for study was 50 deg C. The percentage peak area for the dapsone peak for day zero was taken as 100%; and, accordingly, the percentages were calculated for all the other days. The percentage drug remaining was plotted against time (in days) for all the temperatures, ie, 30, 50, 60, and 70 deg C. The suspension was analyzed for 90 days for physical changes and chemical stability of dapsone. The zero-order rate constants were calculated and plotted against the reciprocal of absolute temperature to obtain the Arrhenius plot. The equation for the straight line was used to calculate the zero-order rate constant at a room temperature of 25 deg C. The shelf life of the suspension was also calculated.

Sample Preparation From the Dapsone Suspension for Stability Study

The suspension was shaken well, and a 1-mL portion was transferred to a 50-mL volumetric flask by the use of a "todeliver" disposable pipet. The tip at the bore of the pipet was wide enough so that the suspension flowed freely through the pipet. The width of the tip of the pipet was important, as the contents of the suspension needed to freely exit the pipet. The inside of the pipet was washed with acetonitrile from a wash bottle so that the washings fell into the volumetric flask, and the contents in the volumetric flask were made up to 50 mL with acetonitrile. This was vortexed for 1.0 to 2.0 minutes using an electric vortex mixer. A 1-mL portion of the solution was transferred to a 20-mL flask to which 5 mL of water had previously been added. A 10-(mu)L portion of this solution was injected into the HPLC system for analysis. Each sample was injected five times, and the samples were taken from three bottles of the suspension that had been stored under specific temperature conditions. The contents of the bottle were shaken well before the suspension was sampled.

Methodology for the Solubility Study for Dapsone

Three samples of dapsone powder weighing 100.5 mg, 112.6 mg, and 80.2 mg were transferred to each of three 25-mL volumetric flasks. The flasks were covered with aluminum-foil wrap to protect the samples from light. These flasks were immersed up to their necks in a water bath with a temperature previously maintained to 35 deg C. A similar procedure was observed at 40, 50, and 60 deg C. The flasks were kept in the water bath for 24 hours. They were then opened, and three 1-mL samples were drawn from the supernatant layer of the suspension, allowing the insoluble drug to settle to the bottom of the flask. Reverse-osmosis water was added to make a 25-mL volume. This last step was done as quickly as possible to minimize the temperature change of the solution. The 1-mL samples of each of the supernatants were transferred to each of the three 50-mL flasks, and reverse-osmosis water was added to make the volume up to 50 mL. Final dilutions were filtered through a 0.2-(mu)m filter and analyzed using the HPLC assay procedure. A similar step-by-step procedure was followed for temperatures at 40, 50, and 60 deg C.

Conclusion

The shelf life for an extemporaneously prepared suspension with a theoretical concentration of 15 mg/mL formulated from commercially available dapsone tablets was calculated to be 31.67 days at 25 deg C and 230.76 days under refrigeration at 4 deg C.

References

1. Nahata MC, Hipple TF. Pediatric Drug Formulations. 2nd ed. Cincinnati, Ohio:Harvey Whitney Books Company; 1992:25.

2. Wade A, ed. MARTINDALE: The Extra Pharmacopoeia. 27th ed. London:The Pharmaceutical Press; 1972:501.

3. Medina I, Mills J, Leoung G, et al. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med 1990;323:776-781.

4. Gatti G, Hossein J, Malena M, et al. Penetration of dapsone into cerebrospinal fluid of patients with AIDS. JAntimicrob Chemother 1997;40:113-115.

5. Kastrup EK. Drug Facts and Comparisons. St. Louis, MO: Drug Facts and Comparisons; 2000:1466-1467.

6. US Pharmacopeial Convention, Inc. United States Pharmacopeia 24/ National Formulary 19. Rockville, MD:United States Pharmacopoeia Convention, Inc.; 2000:496-497.

7. Florey K, ed. Analytical Profiles of Drug Substances. San Diego, CA:The Academic Press, Inc.; 1976;5:88-114.

8. Nahata MC, Morosco RS, Trowbridge JM. Stability of dapsone in two oral liquid dosage forms. Ann Pharmacother2000;34:848-850.

9. Martin AN, Bustamante P, Chun AH. Physical Pharmacy: Physical Chemical Principles in the Pharmaceutical Sciences. 4th ed. Philadelphia, Pennsylvania:Lippincott Williams & Wilkins; 1993:286-289.

10. Carstensen JT, Rhodes CT. Drug Stability Principles and Practices. 3rd ed. New York, New York:Marcel Dekker, Inc.; 2000;107:113-114, 183, 249,252.

Nitin Kaila, MS

Industrial Pharmacy Division

College of Pharmacy

Pharmacy Practice Department

The University of Toledo

Toledo, Ohio

Mohamed El-Ries

The Department of Drug Control Giza, Egypt

A. Riga

Department of Clinical Chemistry

Cleveland State University

Cleveland, Ohio

Kenneth Alexander, PhD, RPh

Industrial Pharmacy Division

College of Pharmacy

The University of Toledo

Toledo, Ohio

D. Dollimore (Posthumously)

Department of Chemistry

The University of Toledo

Toledo, Ohio

Address correspondence to: Kenneth S. Alexander PhD, RPh, The College of Pharmacy, The University of Toledo, Toledo, Ohio 43606. E-mail: kalexan@utnet.utoledo.edu

Copyright International Journal of Pharmaceutical Compounding May/Jun 2003
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