Development of Oral Liquid Dosage Forms of Acetazolamide

Development of Oral Liquid Dosage Forms of Acetazolamide JAGDISH PARASRAMPURIA** AND

v. DASGUPTA*'

Received A ril 19, 1989, from the 'Department of Pharmaceutics, Universit of Houston, Houston, TX 77030. November f4, 1989. *Present address: Abbott Laboratories, Abbott Part, IL 60064. Abstract 0Two oral liquid dosage forms of acetazolamide have been v/v) developed. Usingthe solubility profiles,polyethylene glycol 400 (770, was used as the solubilizingagent and propylene glycol (53%, v/v) as the cosolvent to keep acetazolamide in solution. Because of the bitter taste of acetazolamide, sweetening agents (simple syrup, sorbitol solution, and artificial sweeteners) and flavors (raspberry, sweet, and menthol) were added to the final formulations. A buffer (either phosphateor citrate) solution was used to maintain a pH value of 4 (pH of maximum stability as reportedearlier) to minimize hydrolysis. The final dosage forms were stable for at least 90 days at 37 "C (loss of potency of 5%). According to FDA guidelines, a tentative expiry date of 2 years at 25 "C is justifiable. Acetazolamide i s a diuretic and i s available in a number o f dosage forms such as acetazolamide sodium injection (aspowder) to be reconstituted at the time of administration, sustained release capsules, and tablets. For children who cannot swallow solid dosage forms, an oral liquid dosage form i s essential, but i s not available commercially. In some hospitals a liquid dosage form i s prepared extemporaneously (e.g., University Hospitals, Denver, CO, has two 5 - m g l d acetazolamide suspensions: one consists of 60% sucrose, 1.2% veegum, 0.2% paraben, saccharin, and flavoring agent; the other consists of 5% methyl cellulose instead o f 1.2% veegum). "he stability of acetazolamide in these formulations was not determined. Also, acetazolamide has a very bitter taste which cannot be disguised easily. Acetazolamide i s extremely insoluble in aqueous systems, bitter, and highly sensitive to hydrolysis, which makes it difficult to develop a n oral liquiddosage form for pediatric use. Acetazolamide at a dose o f 5 m g / m L has t o be solubilized by adding solvents which are less polar than water and suitable for oral liquid dosage forms, such as propylene glycol, polyethylene glycol 400, glycerin, and sorbitol(70%, w/w). Asparm e t h y l ester) and simtame (N-L-a-aspartyl-L-phenylalanine ple syrup USP (85%,w/v sucrose) in different proportions are used as sweetening agents. F r o m previous investigations, the results o f preformulation studies were reported,' including the pH o f m a x i m u m stability of -4. The purpose o f these investigations was t o develop a n oral liquid dosage form o f acetazolamide which i s stable for a t least 2 years and has an acceptable taste and appearance.

Experimental Section Chemicals and Reagents-All the chemicals and reagents were USP-NF or ACS grade and were used without further purification. Acetazolamide was supplied by Lederle Laboratories and was used as such. Apparatus-A high-pressure liquid chromatograph (Waters ALC 202) connected to an injector (Rheodyne model 7125), a multiple wavelength detector (Schoffel 7701, and a recorder (Houston Instruments model 1513-12) was used. All pH values were measured with a pH meter (Beckmann's digital model 4500). All the samples for solubility studies were shaken using a temperature-controlled shaker bath (Forma Scientific model 2564). Assay Method-All the assays were conducted using a previously reported stability indicating HPLC method? The microbondapak C18 column (Waters Associates)was the stationary phase for all the assays. Determination of Solubilities of Acetazolamide in Various Solvents and at Various pH Values-The saturated solutions of acetazolamide powder were prepared by shaking the powder with 10 mL each of the 0022-3~9/90/0900-0835$01 .OO/O 0 1990, American Pharmaceutical Association

Accepted for publication

buffers or pure solvent for 24 h in 20-mL test tubes, using a temperaturecontrolled shaker water bath (25 ? 1"C.)The clear solutionswere assayed for acetazolamide using the previously described HPLC assay method.2 Preparation of Dosage Forms-The concentration and the purpose of various ingredients in the final formulations are presented in Table I. Menthol was dissolved in ethanol and acetazolamide was dissolved in polyethylene glycol 400 to which propylene glycol was then added. The above two solutions were mixed together. The artificial sweeteners and both the raspberry and sweet flavors were mixed with simple syrup to which sodium benzoate and the sorbitol solution was added. This was then mixed with the buffer solution to which appropriate quantities of the aqueous solutions of the dyes were previously added. Finally, both the aqueous and propylene glycol solutions were mixed together to obtain the final formulation. After the initial assays, the solutions were divided into two portions. One portion was stored at 37 "C (21"C), and the second at room temperature (25 f 1"C). The solutions were assayed again at appropriate intervals using the previously reported HPLC method.2 Determination of the Effect of Excipients on the Stability of Acetazolamide-Additional formulations were prepared in such a way that they contained everything except some inactive ingredient(s) in order to determine the effect of that particular ingredient(s) on the stability of acetazolamide. Besides the final formulations (A and B), four additional formulations (C-F) were prepared: (C)with all the ingredients except flavors; (D) with all the ingredients except colors; (E) with all the ingredients except preservative; and (F)with all the ingredients except syrup. The exact compositions of these and the final formulations are presented in Table 11. After the initial assays, additional formulations were also divided into two portions and stored at 37 and 25 "C, as explained above. They were reassayed at appropriate intervals using the same HPLC method.2

Results and Discussion The formula for the final formulation of acetazolamide was developed using the information from the solubility profles Table I-Concentration of Various Ingredients in the Final Formulatlon of Acetazolamide (5 rng/mL) Ingredient

Concentration 0.5% (w/v) 7.0% (v/v) 53.0% (V/V) 15.0% (V/V) 15.0% (V/V)

Acetazolamide Polyethylene Glycol 400 Propylene glycol Sorbitol solution (70% w/w) Sucrose solution (simple syrup); 85% w/v Saccharin sodium Aspartame Sodium benzoate FDC Red #40 FDC Blue #1 Raspberry flavor Sweet flavorb Menthol Ethanol

0.18% 0.18% 0.2% 58.8 1.2 0.05%

Purpose Active ingredient Solubilizing agent Cosolvent Sweetening agent Sweetening agent

(w/v) (w/v) (w/v) ppm ppm (V/V) 0.3% (V/V) O.O02%(W/V) 0.5% (v/v)

Buffer solution (phosphate or citrate in water)

0.1

Sweetening agent Sweetening agent Preservative Coloring agent Coloring agent Flavor Flavor Flavor Solubilizing agent for menthol Ma Buffering agent

a Final concentration in the formulation; pH value was 4.0, where the stabilitywas maximum as reportedpreviously (ref 1). Natural pharma sweet flavor, lot 89-107729, Crompton & Knowles Corporation, Fair Lawn, NJ.

Journal of Pharmaceutical Sciences / 835 Vol. 79, No. 9, September 1990

Table Il-Composltlon of the Flnal (A and B) and the Addltlonal Fomulatlons, (C, D, E, and F) Prepared to Study the Effect of Exclplents on the Stablllty of Acetazolamlde

Ingredient Acetazolamide, % wlv PEG 400,Yo v/va Propylene glycol, Yo viv 70% wlw Sorbitol solution, % v/v 85% w/v Sucrose solution,

Formulation A

B

C

D

E

F

15.0 15.0

-

% vlv

Saccharin sodium, Yo wlv 0.175 0.175 0.175 0.175 0.175 0.175 Aspartame, YOw/v 0.175 0.175 0.175 0.175 0.175 0.175 Sodium benzoate, % wlv 0.2 0.2 0.2 0.2 - 0.2 FDC Red #40, ppm 58.8 58.8 58.8 - 58.8 58.8 FDC Blue #1, ppm 1.2 1.2 1.2 - 1.2 1.2 Raspberry flavor, % vlv 0.05 0.05 - 0.05 0.05 0.05 Sweet flavor, YOvlv 0.3 0.3 - 0.3 0.3 0.3 Menthol, YOw/v 0.002 0.002 - 0.002 0.002 0.002 Alcohol, % vh, 0.5 0.5 - 0.5 0.5 0.5 Phosphate buffer solution, 0.1 - 0.1 0.1 0.1 0.1 Mb

Citrate buffer solution, Mb

-

0.1

-

-

-

-

Polyethylene glycol 400. Final concentration; the pH was 4,where the acetazolamide has maximum stability as reported previously (ref 1). a

(Table III) and the preformulation studies reported earlier.1 Preliminary investigations indicated that polyethylene glycol 400 or propylene glycol did not affect the stability of acetazolamide adversely. The other excipienta present had no effect on stability of acetazolamide (Tables IV and V). Although bitter, polyethylene glycol 400 was required to dissolve acetazolamide and to keep it in solution. The solubility of acewlamide was very high (87.8 mg/mL) in PEG 400 versus only 7.4 mg/mL in propylene glycol. The solubility of acetazolamide was also high above pH 8.2, however its hydrolysis also increases many fold;l therefore, the solubility on the basic side of the pH scale was not useful for development of the final dosage form. Stability of Final Formulations-Formulations A and B are both the final formulations with a difference of buffering agent only. Formulation A contains phosphate buffer versus B which contains citrate butfer (Table 11).It is obvious (Table IV)that acetazolamide did not decompose significantly at 25 "C in 178 days. Therefore, the data at 25°C was not very useful for determining the Kobevalue. However, at 37 "C,the h a 1 formulations (A and B) did decompose by
Solution or Solvent Aqueous phosphate buffer

Polyethylene glycol 400 Propylene glycol Alcohol Glycerin Water

PH 1.68 3.19 4.01 4.98 5.27 5.47 6.06 6.85 8.17

-

-

-

Solubility,mglmLa 1.26(0.02) 1.08(0.02) 1.17(0.02) 0.80(0.01) 0.87(0.02) 0.82(0.01) 0.89 (0.02) 1.01 (0.02) 2.79(0.03) 87.81 (3.45) 7.44(1.20) 3.93(0.11) 3.65(0.09) 0.72(0.05)

a Mean (2SD)based on two assay readings of each of three samples (total of six assays).

830 I Journal of Pharmaceutical Sciences Vol. 79, No. 9, September 1990

Percent Retaineda after Various Number of Days (Based on 100% on Day Zero)b

Formulation

0.5 0.5 0.5 0.5 0.5 0.5 7.0 7.0 7.0 7.0 7.0 7.0 53.0 53.0 53.0 53.0 53.0 53.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0 15.0

Table IV-Assay Results of Acetazolamlde Formulations Stored at 25 ( i l )"C

A

B C D E

F

60

119

150

1 78

98.39 (2.78) 97.34 (0.84) 100.85 (0.96) 100.71 (1.49) 101.04 (2.11) 98.99 (1.12)

97.13 (1.68) 97.54 (0.65) 98.08 (0.64) 99.44 (1.26) 100.46 (0.83) 98.76 (1.82)

97.26 (1.27) 97.84 (0.45) 97.79 (0.85) 98.38 (1.06) 99.89 (0.45) 98.68 (1.36)

98.60 (1 34) 97.50 (0.98) 97.08 (2.70) 98.00 (0.36) 99.67 (1.78) 97.86 (0.95)

a Mean (4SD)based on two assay readings of each of three samples (total of six assays). All the solutions were clear throughout the study period; the pH values of solutions did not change; SD are given in parentheses.

Table V-Assay 37 (*I) "C

Formulation

Results of Acetazolamlde Formulations Stored at

Percent Retained" after Various Number of Days (Based on 100% on Day Zero)b 26

A

B C

D E F

61

97.51 (1.66) 97.29 (0.26) 96.78 (1.01) 99.12 (1.04) 99.24 (0.95) 97.88 (1.81)

96.77 (1 -24) 95.92 (1.09) 94.26 (1 55) 96.21 (1.35) 97.50 (1.43) 97.38 (1.75)

90

120

94.88 (1.24) 95.06 (0.93) 93.70 (0.24) 95.57 (2.74) 97.01 (2.31) 96.09 (1.28)

92.98 (0.96) 95.54 (0.46) 92.91 (0.79) 93.91 (0.48) 95.36 (0.68) 94.09 (1.09)

151 92.58 (0.36) 93.08 (0.92) 91.79 (0.78) 91.96 (0.44) 93.83 (0.38) 92.57 (0.87)

179 90.64 (1.05) 90.48 (1.47) 89.79 (0.59) 89.69 (0.85) 91.96 (0.76) 90.60 (0.56)

a Mean (-tSD)based on two assay readings of each of three samples (total of six assays). All the solutions were clear throughout the study period; the pH values of solutions did not change; SD given in parentheses.

It is generally accepted that a formulation is considered potent if the potency is between -C 10%.Furthermore, according to the guidelinesby the FDA: if a product is stable for 90 days at 37 "C (relative humidity of 75%or more), a 2 years expiry date C M be used. In these studies, the final formulationswere stable for 179 days at 37 "C (lossin potency of 2 years at 25 "C. In conclusion, it is apparent that reasonably stable oral liquid dosage forms of acetazolamide can be formulated which can be used for small children and infants. The two final formulations (A & B) developed are equally good, with a difference of only the buffering agent.

References and Notes 1. Parasrampuria,J.; Gupta,V. D. J.Phurm. Sci. 1989,78,855-857. 2. Gu ta, V. D.; Parasrampuria,J.DrugDevel. Ind. Pharm. 1987,13,

147-157. 3. FDA, Draft of Guidelines for Stability Studies for Human Drugs and Biologics, August, 1985.

Acknowledgments Presented at the Fo$h.Annual Meetin ofthe American Association of Pharmaceutical Scientists on October g3, 1989,in Atlanta, GA.