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Determination of Ibuprofen Vapor Pressure at Temperatures of Pharmaceutical Interest
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Determination of Ibuprofen Vapor Pressure at Temperatures of Pharmaceutical Interest To the Editor: Ibuprofen is a nonsteroidal anti-inflammatory agent that is available in a variety of prescription and nonprescription drug products. Recently, during excipient compatibility studies, it was noted that glass vials containing solid ibuprofen developed a haze on their inner walls when stored a t 40 "C. Although it is generally believed in the pharmaceutical industry that ibuprofen sublimes during storage, there are currently no published values for the vapor pressure of the compound. This information would be of interest from a physical, and perhaps chemical, stability standpoint. We have, therefore, measured the vapor pressure of ibuprofen a t temperatures of pharmaceutical interest; that is, temperatures such as might be attained during drying and coating processes or be used for accelerated stability testing. The propensity of ibuprofen to sublime during storage at elevated temperatures was demonstrated by placing a small amount of solid ibuprofen (USP grade, Upjohn Pharmaceutical Company, Kalamazoo, MD into a 250-mL round-bottomedflask. The neck of the flask was fitted with a water-cooled condenser to minimize the escape of ibuprofen vapor. The apparatus was evacuated and the flask was immersed in a 60 "Cwater bath for a period of 24 h. ARer that time, a residue was visible around the neck of the flask. A sample of the sublimate was isolated, dissolved in an appropriate solvent, and analyzed by mass spedrometry. The resulting spectrum exhibited all of the significant fragment ions present in the mass spectrum of ibuprofen reference material. The vapor pressure of ibuprofen was measured by the Knudsen effusion technique.1.2 Briefly, this technique uses gravimetric analysis to monitor the rate of vapor loss through a small orifice under conditions of free molecular diffusion. Under these conditions, the vapor pressure of a material and the rate of mass loss are related by the Knudsen equation:
-
Pa = 7.9362 x lo-* RdAo(T/My (1) where Pa is the apparent vapor pressure (mmHg), Ro is the effusion rate (mg min-'1, T is the absolute temperature, M is the molecular weight of the effusing material, and A, is the area of the orifice (cm2). Normally, a t least two different orifice sizes are used to rule out association or dissociation of the effusing species in the vapor phase. The equilibrium vapor pressure (Pa)is calculated from eq 2:
-
P, = P,(ltK, + AdAs) (2) where A, is the area (cm2)ofthe surface containing the orifice and K, is the Clausing factor for the orifice. The value of the latter term is dependent on the orifice size. Vapor pressure values for solid ibuprofen were determined at temperatures ranging from 23 to 64 "C. The vapor pressure of a solid is related to the temperature by the ClausiusClapeyron equation: dP/dT = AH,,$tRT2 (3) where R is the gas constant; and AHsubis the heat or enthalpy of sublimation. If the enthalpy of sublimation is independent of temperature, eq 3 integrates to eq 4: In P
=
-AH,,dRT
552 / Journal of fharmaceuficai Sciences Vol. 79, No. 6, June 1990
+C
(4)
2'
8
10-3
6.
42-
0,
I
E E
10"; 64-
2-
10-J; 6-
IOOO/K Flgure I-Ibuprofen vapor pressure data plotted according to eq 4. Key: (0)0.2580-cm orifice; (0)0.0592-cm orifice.
where C is a constant of integration. The ibuprofen vapor pressure-temperature data obey eq 4 very well, as shown in Figure 1. The enthalpy of sublimation, calculated from the slope of the least-squaresline fit to the data, is 121 kJ * mol-l. Although ibuprofenexertsa negligiblevapor pressure at 25 "C (9 x mmHg), the value increases by several orders of magnitude as the temperature is increased. At higher temperatures, therefore, the rate at which ibuprofen solid is lost to the vapor phase becomes significant. For example, at 55"C, the measured weight loss rate was 4.15 mg day-'. This rate was measured under high vacuum conditions;however,it emphasizes that it may be necessary to consider the tendency of ibuprofen to sublime when designing manufacturing processes or stability protocols.
References and Notes 1. Davies, M.; Kybett, B. Trans. Furuduy SOC.1965,61,1608-1617. 2. Pikal, M. J.; Lukes, A. L. J . Phurm. Sci. 1976, 65, 1269-1284.
K. D. ERTEL*X R. A. HEASLEY* C. KOEGEL* A. CHAKRABARTI* J. T. CARSTENSEN§ 'Merrell Dow Research Institute Cincinnati, OH 45215 *Dow Chemical U S A . Midland, MI 48674 §School of Pharmacy University of Wisconsin Madison, WI 53706 Received July 5, 1989. Accepted for publication August 30,1989. 0022-3549/90/0600-0552$0 1.OO/O 0 7990, American Pharmaceutical Association
Determination of Ibuprofen Vapor Pressure at Temperatures of Pharmaceutical Interest To the Editor: Ibuprofen is a nonsteroidal anti-inflammatory agent that is available in a variety of prescription and nonprescription drug products. Recently, during excipient compatibility studies, it was noted that glass vials containing solid ibuprofen developed a haze on their inner walls when stored a t 40 "C. Although it is generally believed in the pharmaceutical industry that ibuprofen sublimes during storage, there are currently no published values for the vapor pressure of the compound. This information would be of interest from a physical, and perhaps chemical, stability standpoint. We have, therefore, measured the vapor pressure of ibuprofen a t temperatures of pharmaceutical interest; that is, temperatures such as might be attained during drying and coating processes or be used for accelerated stability testing. The propensity of ibuprofen to sublime during storage at elevated temperatures was demonstrated by placing a small amount of solid ibuprofen (USP grade, Upjohn Pharmaceutical Company, Kalamazoo, MD into a 250-mL round-bottomedflask. The neck of the flask was fitted with a water-cooled condenser to minimize the escape of ibuprofen vapor. The apparatus was evacuated and the flask was immersed in a 60 "Cwater bath for a period of 24 h. ARer that time, a residue was visible around the neck of the flask. A sample of the sublimate was isolated, dissolved in an appropriate solvent, and analyzed by mass spedrometry. The resulting spectrum exhibited all of the significant fragment ions present in the mass spectrum of ibuprofen reference material. The vapor pressure of ibuprofen was measured by the Knudsen effusion technique.1.2 Briefly, this technique uses gravimetric analysis to monitor the rate of vapor loss through a small orifice under conditions of free molecular diffusion. Under these conditions, the vapor pressure of a material and the rate of mass loss are related by the Knudsen equation:
-
Pa = 7.9362 x lo-* RdAo(T/My (1) where Pa is the apparent vapor pressure (mmHg), Ro is the effusion rate (mg min-'1, T is the absolute temperature, M is the molecular weight of the effusing material, and A, is the area of the orifice (cm2). Normally, a t least two different orifice sizes are used to rule out association or dissociation of the effusing species in the vapor phase. The equilibrium vapor pressure (Pa)is calculated from eq 2:
-
P, = P,(ltK, + AdAs) (2) where A, is the area (cm2)ofthe surface containing the orifice and K, is the Clausing factor for the orifice. The value of the latter term is dependent on the orifice size. Vapor pressure values for solid ibuprofen were determined at temperatures ranging from 23 to 64 "C. The vapor pressure of a solid is related to the temperature by the ClausiusClapeyron equation: dP/dT = AH,,$tRT2 (3) where R is the gas constant; and AHsubis the heat or enthalpy of sublimation. If the enthalpy of sublimation is independent of temperature, eq 3 integrates to eq 4: In P
=
-AH,,dRT
552 / Journal of fharmaceuficai Sciences Vol. 79, No. 6, June 1990
+C
(4)
2'
8
10-3
6.
42-
0,
I
E E
10"; 64-
2-
10-J; 6-
IOOO/K Flgure I-Ibuprofen vapor pressure data plotted according to eq 4. Key: (0)0.2580-cm orifice; (0)0.0592-cm orifice.
where C is a constant of integration. The ibuprofen vapor pressure-temperature data obey eq 4 very well, as shown in Figure 1. The enthalpy of sublimation, calculated from the slope of the least-squaresline fit to the data, is 121 kJ * mol-l. Although ibuprofenexertsa negligiblevapor pressure at 25 "C (9 x mmHg), the value increases by several orders of magnitude as the temperature is increased. At higher temperatures, therefore, the rate at which ibuprofen solid is lost to the vapor phase becomes significant. For example, at 55"C, the measured weight loss rate was 4.15 mg day-'. This rate was measured under high vacuum conditions;however,it emphasizes that it may be necessary to consider the tendency of ibuprofen to sublime when designing manufacturing processes or stability protocols.
References and Notes 1. Davies, M.; Kybett, B. Trans. Furuduy SOC.1965,61,1608-1617. 2. Pikal, M. J.; Lukes, A. L. J . Phurm. Sci. 1976, 65, 1269-1284.
K. D. ERTEL*X R. A. HEASLEY* C. KOEGEL* A. CHAKRABARTI* J. T. CARSTENSEN§ 'Merrell Dow Research Institute Cincinnati, OH 45215 *Dow Chemical U S A . Midland, MI 48674 §School of Pharmacy University of Wisconsin Madison, WI 53706 Received July 5, 1989. Accepted for publication August 30,1989. 0022-3549/90/0600-0552$0 1.OO/O 0 7990, American Pharmaceutical Association