Exchange of Comments: Repetitive Determination of Isonicotinic Acid Hydrazide in Flow-Through Systems by Series Reactions Sir: We read with interest the recent paper by Dutt and Mottola (I) where a procedure is proposed for the repetitive analysis of isonicotinic hydrazide. The procedure is reported to be rapid, highly selective, and particularly applicable where an automated procedure is indicated. We wish to comment on that aspect of the report which concerns the application to pharmaceutical dosage forms. The authors employed the USP XVIII method ( 2 ) which involves an iodometric titration procedure. This method was found to be inapplicable for dosage forms containing reducing sugars as excipients. As a result of a comparative study of four commonly used assay procedures (3), the nitrite titration was adopted in USP XIX ( 4 ) which has been official since July 1, 1975. The nitrite method does not suffer from the drawbacks noted for the iodometric method. T h e authors appear to be confused about compendial specifications. In the last sentence of their paper they state "The content of isoniazid found per tablet was, however, consistently lower than the minimum 98.0% stipulated by the USP XVIII.'. While the potency statement for the drug entity, Isoniazid USP, is "not less than 98.0 percent-."; "Isoniazid Tablets contain not less than 93.0 percent and not more than 107.0 percent of the labeled amount of C6H7N30." T h e authors apparently conducted single tablet assays, whereas the officialprocedure calls for samples obtained from a powder mass representative of not less than 20 tablets. Furthermore,
the monograph includes a Content liniformity specification ( 4 ) . This is a test for homogeneity based on the individual tablet analysis of 10 tablets. T h e specification is met if the content of each of the 10 tablets falls within the limits of 85.0 percent and 115.0 percent of the average of the potency limits specified in the monograph. Under certain conditions it is even possible for the specification to be met if a single tablet falls within the range of 75.0 percent and 125.0 percent of the average of the potency limits specified in the monograph.
Sir: Two distinctive elements can be identified in Fitzloff and Blake's note. They: 1)point out that in the XIX Edition of the USP the nitrite method has been adopted for isoniazid determination, and, 2) make reference to a misquote in the last paragraph of our paper ( I ) . We concede that a t the time of performing the work reported in our paper, we had access to the XVIII Edition of USP, but the XIX Edition was not yet in our library. We did, however, indicate in the introduction (reference 17 in our paper) that Blake et al. ( 2 ) compared four widely used standard methods and recommended the nitrite method on the basis of recoveries obtained in the presence of glucose, sucrose, lactose (this corresponds to reference 3 in their comments). It shall be pointed out that for the particular case of tablets, the iodometric procedure seems to give satisfactory results for comparison since interfering sugars, if present, do not cause serious problems as might be the case with samples normally containing higher amounts of sugar, such as syrups. Blake et al. ( 2 ) provided results pointing in this direction (Table in p 1304 there) and went further concluding that ( p 1305) "Consistent results were obtained for the analysis of the tablet dosage form by the four methods." In their comments on our limited application to tablets, Fitzloff and Blake disclosed a misquote in the last paragraph of our paper (I). Their comments on cornpendial specifications are well taken and we apologize to the readers for failing to correct this on time. We reported results for three tablets but collected data for more tablets and in most instances (9 out
of 10) the percent content was lower than 93.0. With respect to this, and as indicated earlier ( I ) , in our method the presence of common diluents, such as sugars, starch, citric and oxalic acid, exert no interference even if present in a thousandfold excess with respect t o isoniazid. We hope these comments clarify t,he matter and reiterate our belief that the determination proposed by us is simpler, faster, and more easily adapted to automation than other reported methods, particularly if compared with the nitrite titration as it is specified in XIX USP (3).
LITERATURE CITED (1) V . V. S. Eswara Dutt and H. A . Mottola, Anal. Chern., 49, 776 (1977). (2) "The United States Pharmacopeia", 18th rev., Mack Publishing Co., Easton. Pa., 1970 p 349. (3) M. I. Blake, D. Bode, and H.J. Rhodes, J . Pharm. Sci., 63, 1303 (1974). (4) "The United States Pharmacopeia", 19th rev, Mack Publishing Co., Easton, Pa., 1975, pp 273, 648.
J. F. Fitzloff Department of Medicinal Chemistry
M. I. Blake* Department of Pharmacy University of Illinois a t the Medical Center Chicago, Illinois 60612
RECEIVED for review May 20,1977. Accepted August 29,1977.
LITERATURE CITED (1) V. V. S.Eswara Dutt and H. A. Mottola, Anal. Chern., 49, 776 (1977). (2) M. I. Blake, D. Bode, and H. J . Rhodes, J . pharm. S c i , 63,1303 (1974). (3) "The United States Pharmacopeia," 19th rev., Mack Publishing Co.. Easton, Pa., 1975.
V. V. S. Eswara Dutt Department of Health and Human Ecology California State College San Bernardino, California 92407
Horacio A. Mottola* Department of Chemistry Oklahoma State University Stillwater, Oklahoma 74074
RECEIVED for review July 8, 1977. Accepted August 29, 1977.
ANALYTICAL CHEMISTRY, VOL. 49, NO. 14, DECEMBER 1977
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