Abstract
In the present study, use of hexagonal urea as a means for the reduction in moisture sensitivity/uptake has been investigated using nicorandil as a model endocytic drug. Urea, a well-known adductor for linear compounds, was successfully employed for adduction of nicorandil—a substituted cyclic organic compound through recently reported technique. Formation of urea inclusion compounds was confirmed by Fourier transform infrared, differential scanning calorimetry (DSC) and X-ray diffraction. Modified Zimmerschied calorimetric method was employed for estimation of the minimum amount of rapidly adductible endocyte (RAE) required per unit weight of nicorandil for adduction in urea. Urea–nicorandil–RAE inclusion compounds containing varying proportions of guests were prepared and their thermal behavior studied by DSC. However, coinclusion of nicorandil—a normally non-adductible endocytic compound in urea—naturally resulted in distortion of narrow channels of hexagonal lattice leading to the formation of distorted hexagonal urea. Both the normal and distorted hexagonal urea revealed appreciable reduction in moisture uptake when compared to that of tetragonal urea. The distorted urea framework exhibited increased moisture uptake as compared to the non-distorted one. Study also revealed improved stability of included nicorandil upon exposure to atmosphere at higher humidity levels. The coinclusion compounds of nicorandil were found to exhibit good content uniformity. Urea inclusion compounds of nicorandil in the presence of suitable RAE can be a promising alternative for the development of stable formulations of the drug.
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References
Kontny MJ, Zografi G. Sorption of water by solids. In: Brittain HG, editor. Physical characterization of pharmaceutical solids. New York: Marcel Dekker; 1995. p. 387–418.
Yoshioka S, Stella VJ, editors. Stability of drugs and dosage forms. Berlin: Springer; 2006. pp. 106–107.
Trissel L, editor. Triessel’s stability of compounded formulations. 11th edn. Washington, DC: American Pharmaceutical Association; 2002.
Kirk RE, Othmer DF, editors. Kirk-Othmer Encyclopedia of chemical technology, vol. 23. 3rd edn. New York: Wiley-Interscience; 1982. pp. 548–574.
Adams JR, Merz AR. Hygroscopicity of fertilizer materials and mixtures. Ind Eng Chem 1929;21:4–9.
Harris KDM. Fundamental and applied aspects of urea and thiourea inclusion compounds. Supramol Chem 2007;9:47–53.
Bishop R, Dance IG. New type of helical inclusion networks. Topics Current Chem 1988;149:139–88.
Frank SG. Inclusion compounds. J Pharm Sci 1975;64:1585–604.
Hollingsworth MD, Harris KDM. Urea inclusion compounds. In: Atwood JL, et al, editor. Comprehensive supramolecular chemistry. Solid state supramolecular chemistry—crystal engineering, vol. 6. New York: Pergamon; 1996. p. 177–237.
Takemoto K, Sonoda N. Inclusion compounds of urea, thiourea and selenourea. In: Atwood JL, Davis JED, MacNicol DD, editors. Inclusion compounds, vol. 2. New York: Academic; 1984. p. 47–67.
Schlenk W. Urea addition of aliphatic compounds. Justus Liebigs Ann Chem 1949;565:204–40.
Findlay RA. Adductive crystallization. In: Schoen HM, Mcketta JJ, editors. New chemical engineering separation techniques. New York: Interscience Publishers; 1962. p. 257–318.
McAdie MG. Thermal decomposition of molecular complexes. Can J Chem 1963;41:2144–53.
Thakral S, Madan AK. Topological models for prediction of heat of decomposition of urea inclusion compounds containing aliphatic endocytes. J Inclusion Phenom Macrocyclic Chem 2008;60:187–92.
Frampton J, Buckley M, Flitton A. Nicorandil a review on its pharmacology and therapeutic efficacy in angina pectoris. Drugs 1992;44:625–55.
Camm AJ, Maltz MB. A controlled single-dose study of efficacy, dose response and duration of action of nicorandil in angina pectoris. Am J Cardiol 1989;20:61J–5J.
Reddy KR, Mutanik S, Reddy S. Once-daily sustained release matrix tablets of nicorandil: formulation and in-vitro evaluation. AAPS Pharm Sci Tech. 2003;4(4), article 61.
Frydman A, et al. Pharmacokinetics of nicorandil. Am J Cardiol 1989;63:25J–33J.
Tipre DN, Vavia PR. Formulation optimization and stability study of transdermal therapeutic system of nicorandil. Pharm Develop Tech 2002;7:325–32.
Veronesi PA, Veronesi AM. Pharmaceutically storage stable nicorandil formulations. United States Patent 5,580,576; 1996.
Iida Y, Takashi T, Shuji S. Method of production of stable nicorandil preparation. Canadian Patent 497,114; 1989.
Iida Y, Takashi T, Shuji S. Method of production of stable nicorandil preparation. United States Patent 4,803,213; 1989.
Tipre DN, Vavia PR. Stabilization of nicorandil with cyclodextrin for oral and parenteral dosage form. Tenth International Symposium on Recent Advances in Drug Delivery Systems, Salt Lake City, UT, February 19–22, 2001, Abstract, 132–133.
Thakral S, Madan AK. Adduction of amiloride hydrochloride in urea through a modified technique for the dissolution enhancement. J. Pharm Sci 2008;97:1191–201.
Thakral S, Madan AK. Urea inclusion compounds of enalapril maleate for improvement of pharmaceutical characteristics. J Pharm Pharmacol 2007;59(11):1501–7.
Thakral S, Madan AK. Urea inclusion compounds of glipizide for improvement in dissolution rate. J Inclusion Phenom Macrocyclic Chem 2008;60(3–4):203–9.
Thakral S, Madan AK. Indian Provisional patent “Urea based inclusion complexes of nicorandil, carvidilol, gliclazide and glipizide and the processes thereof.” Indian Patent Application Number 208/DEL/2007 filed on 01/02/2007; 2007.
Madan AK. Microencapsulation of low dose drugs. Ph.D. Thesis, IIT Delhi; 1994.
Madan AK, Grover PD. A process for preparation of urea based inclusion compounds of Vitamin A esters. Indian Patent 180627, 20 Jan; 1993.
Bajaj V, Madan AK. A process for preparation of urea complexes of vitamin E and its esters. Indian Patent 182620, 24 Oct; 1994.
Bajaj V, Madan AK. Highly distorted urea based channel lattice complexes as analternative to solid dispersions for improving content uniformity and dissolution rate. 14 the Conference of Biomedical Engineering society Of India IEEE.15–18th Feb, New Delhi, Published on 4/67–4/68; 1995.
Zimmerschied WJ, et al. Crystalline adducts of urea with linear aliphatic compounds. Ind Eng Chem 1950;42:1300–6.
Nyqvist H. Saturated salt solutions for maintaining specified relative humidities. Int J Pharm Tech Prod Mfr 1983;4:47–8.
Fischer PHH, McDowell CA. The infrared absorption spectra of urea-hydrocarbon adduct. Can J Chem 1960;38:187–93.
Durie RA, Harrisson RJ. Effect of urea-adduct formation and physical state on the infrared spectra of n-paraffin hydrocarbons. Spectrochemica Acta 1962;18:1505–14.
Keller WE. Evidence of planer structure of urea. J Chem Phys 1948;16:1003–4.
Davies JED. Spectroscopic studies of inclusion compounds. In: Atwood JW, Davies JED, MacNicol DD, editors. Inclusion compounds vol. 3. London: Academic; 1984. p. 41.
White MA. Origins of thermodynamic stability of urea: alkane inclusion compounds. Can J Chem 1988;76:1695–8.
Radell J, Brodman BW. Urea inclusion compounds of alkenoic acids and alkyl alkenoates. Can J Chem 1965;43:304–5.
Brodman BW, Radell J. X-ray Powder diffraction patterns of some n-alkanone urea inclusion compounds. Separation Sci 1967;2:139–42.
Radell J, Connolly JW. Determination of relative stability of urea complexes from X-ray powder diffraction data. In: Muller WM, editor. Advances in X-ray analysis, vol. 4. New York: Plenum; 1961. p. 140–50.
Acknowledgment
The authors are highly thankful to IIT, New Delhi, for allowing us to conduct XRD analysis of the samples, and to Roorki Research and Analytical Labs, for conducting HPLC analysis.
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Thakral, S., Madan, A.K. Reduction in Moisture Sensitivity/Uptake of Moisture Sensitive Drugs Through Adduction in Urea. J Pharm Innov 3, 249–257 (2008). https://doi.org/10.1007/s12247-008-9045-z
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DOI: https://doi.org/10.1007/s12247-008-9045-z