Assessing Drug-Excipient Interactions in the Formulation of Isoniazid Tablets

Wollinger, Wagner; Silva, Raphael A. da; Nóbrega, Andréa B. da; Lopes, Rosangela S. C.; Lopes, Claudio C.; Slana, Glaucia B. C. A.

doi:10.5935/0103-5053.20150334

Wagner Wollinger ^**e-mail: wwollinger@inmetro.gov.br

Instituto Nacional de Metrologia, Qualidade e Tecnologia (Inmetro), 25250-020 Duque de Caxias-RJ, Brazil

Raphael A. da Silva

Faculdade Anhanguera de Brasília, 71950-550 Taguatinga-DF, Brazil

Andréa B. da Nóbrega

Fundação Oswaldo Cruz (FIOCRUZ), 22775-903 Rio de Janeiro-RJ, Brazil

Rosangela S. C. Lopes

Instituto de Química, Universidade Federal do Rio de Janeiro (UFRJ), 21941-909 Rio de Janeiro-RJ, Brazil

Claudio C. Lopes

Instituto de Química, Universidade Federal do Rio de Janeiro (UFRJ), 21941-909 Rio de Janeiro-RJ, Brazil

Glaucia B. C. A. Slana

Instituto Nacional da Propriedade Industrial (INPI), 20090-910 Rio de Janeiro-RJ, Brazil

*e-mail: wwollinger@inmetro.gov.br

Figures (6)
Tables (1)

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Figure 1
Chromatograms showing isoniazid (INH) profile using the following diluents: (a) MeOH; (b) MeOH 4% in buffer. Chromatographic parameters as described in USP:⁵5 United States Pharmacopeia, US Phamacopeia 34, United States Pharmacopeial Convention: Rockville, 2011. column C18 Symmetry Shield, mobile phase at 1.5 mL min^-1, gradient of acetonitrile (ACN) in buffer starting at 4% (0-5 min), increasing from 4 to 55% (5-6 min) and keeping at 55% up to 15 min.

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Figure 2
Ionization of isoniazid (INH) and related substances according to pH.

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Figure 3
Role of C18 stationary phase on separation of isoniazid (INH)/isonicotinamide (INAAM) and INH peak shape. Mobile phase constituted of 4% acetonitrile (ACN) in buffer at pH 6.8, flow rate 0.5 mL min^-1. Error bars correspond to standard deviation (n = 3).

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Figure 4
Chromatogram obtained in optimized conditions for isoniazid (INH) and related impurities. C18 Symmetry Shield, buffer at pH 6.8: acetonitrile (ACN) 96:4; flow rate 0.8 mL min^-1.

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Figure 5
Drug-compatibility study at 40 ºC and 75% of relative humidity. All the samples contained isoniazid (INH) and the excipient(s) described. Isonicotinic acid (INA) and isonicotinamide (INAAM) were not detected in the sample that contained INH only, as well as in the mixtures of INH with the following excipients: 102 microcrystalline cellulose, sodium starch glycolate, polyvinylpyrrolidone, colloidal silicon dioxide, Eudragit^®, talc powder 325 mesh, and polyethylene glycol 6000.

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Figure 6
Chemical structures of Ponceau 4R (CAS 2611-82-7, present in FD&C red 6 lake) and indigocarmine (CAS 860-22-0, present in FD&C blue 2 lake).

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Table 1
Retention factor (k’) for isoniazid (INH), isonicotinamide (INAAM) and isonicotinic acid (INA) according to stationary and mobile phase

Column	Experiment	Mobile phase	k'^a a flow rate = 0.5 mL min−1;
Column	Experiment	Mobile phase	INA	INH	INAAM
Hypersil C18	1	water (pH 6.8):ACN 96:4	0.03 ± 0.01	1.39 ± 0.03	1.79 ± 0.03
Hypersil C18	2	water (pH 2.5):ACN 96:4	0.76 ± 0.03	0.76 ± 0.03	0.76 ± 0.02
C8	3	water (pH 6.8):ACN 96:4	0.05 ± 0.01	2.16 ± 0.04	2.88 ± 0.03
C8	4	water (pH 2.5):ACN 96:4	0.69 ± 0.03	0.31 ± 0.03	0.31 ± 0.03
Nitrile	5	water (pH 6.8):ACN 96:4	0.15 ± 0.02	0.15 ± 0.02	0.15 ± 0.02
Nitrile	6	water (pH 2.5):ACN 96:4	0.08 ± 0.01	0.56 ± 0.03	0.56 ± 0.04
Phenyl	7	water (pH 6.8):ACN 96:4	1.06 ± 0.04	1.06 ± 0.05	1.06 ± 0.04
Phenyl	8	water (pH 2.5):ACN 96:4	1.15 ± 0.03	1.15 ± 0.04	1.15 ± 0.03
Hypersil C18 with anionic pairing	9	water:HS 0.1%:ACN 60:30:10	0.56 ± 0.02	1.46 ± 0.04	1.21 ± 0.03
Hypersil C18 with anionic pairing	10	exp. 9 + 0.1% TEA	0.52 ± 0.02	1.13 ± 0.03	0.94 ± 0.04
Hypersil C18 with cationic pairing	11	TBA 25 mmol L^-1, pH 2.5b	1.33 ± 0.06	0.53 ± 0.03	0.53 ± 0.03
	12	TBA 25 mmol L^-1, pH 6.8^b b TBA solution: ACN:MeOH, 96:2:2; ACN: acetonitrile; HS: sodium 1-heptanesulfonate; TEA: trimethylamine; TBA: tetrabutylammonium hydroxide; PBS: phosphate buffer. Average (n = 3) ± confidence interval (95%).	6.71 ± 0.10	0.96 ± 0.03	1.40 ± 0.07
	13	TBA 12 mmol L^-1, pH 6.8^b b TBA solution: ACN:MeOH, 96:2:2; ACN: acetonitrile; HS: sodium 1-heptanesulfonate; TEA: trimethylamine; TBA: tetrabutylammonium hydroxide; PBS: phosphate buffer. Average (n = 3) ± confidence interval (95%).	9.24 ± 0.09	1.13 ± 0.04	1.48 ± 0.05
	14	TBA 5 mmol L^-1, pH 6.8^b b TBA solution: ACN:MeOH, 96:2:2; ACN: acetonitrile; HS: sodium 1-heptanesulfonate; TEA: trimethylamine; TBA: tetrabutylammonium hydroxide; PBS: phosphate buffer. Average (n = 3) ± confidence interval (95%).	11.62 ± 0.07	1.23 ± 0.05	1.55 ± 0.04
	15	exp. 14 + 0.020 mol L^-1 PBS	5.95 ± 0.05	0.91 ± 0.03	1.36 ± 0.03
Hypersil C18	16	PBS (pH 6.8):ACN 96:4	0.50 ± 0.02	1.45 ± 0.05	2.05 ± 0.10
Spherisorb C18	17	PBS (pH 6.8):ACN 96:4	0.54 ± 0.02	1.48 ± 0.05	2.07 ± 0.10
Ace 5 C18	18	PBS (pH 6.8):ACN 96:4	0.55 ± 0.03	1.52 ± 0.04	2.14 ± 0.04
Symmetry Shield C18	19	PBS (pH 6.8):ACN 96:4	0.45 ± 0.02	1.35 ± 0.03	2.04 ± 0.03

[1] *e-mail: wwollinger@inmetro.gov.br

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Assessing Drug-Excipient Interactions in the Formulation of Isoniazid Tablets