Abstract
The mechanism of l-Val on how to improve the stability of gabapentin (GBP) was described by the combination of chemical analysis experiments and computer simulations. Scanning electron microscope (SEM), powder X-ray diffraction (PXRD), and differential scanning calorimeter (DSC), coupled with attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), were used to identify β-GBP prepared by rapid solvent removal method. The reaction barriers on crystal planes, β-GBP (100) and β-GBP (10-1), are smaller than α-GBP and γ-GBP, reaching 276.65 kJ/mol and 299.57 kJ/mol, respectively. Thus, it was easier for β-GBP to form lactam, and the occurrence of β-GBP would lead the worse stability of α-GBP. The addition of neutral amino acids such as l-Val could improve the stability of α-GBP effectively. The adsorption energy of α-GBP (002) crystal plane with l-Val is larger than that of other crystal planes, reaching 42.17 kJ/mol. Hydrogen bond was the combination of l-Val and GBP main crystal planes, which could inhibit the crystal transformation of α-GBP. These results suggest that neutral amino acid protectants, such as l-Val, could improve the stability of α-GBP effectively, and inhibition of crystal transformation is one of the effective methods to improve the stability of polymorphic drugs.
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References
Zong Z, Desai SD, Kaushal AM, Barich DH, Huang H, Munson EJ, et al. The stabilizing effect of moisture on the solid-state degradation of gabapentin. AAPS PharmSciTech. 2011;12(3):924–31.
Herrmann M, Menz J, Olsson O, Kümmerer K. Identification of phototransformation products of the antiepileptic drug gabapentin: biodegradability and initial assessment of toxicity. Water Res. 2015;15(85):11–21.
Kansal S, Sinha P, Agarwa R, Sharma V. Comparison of analgesic efficacy of antiepileptic gabapentin with conventional analgesic diclofenac in rat experimental models. J Drug Deliv Ther. 2017;1(7):44–8.
Singh D, Kennedy DH. The use of gabapentin for the treatment of postherpetic neuralgia. Clin Ther. 2003;25(3):852–89.
Hsu CH, Ke WT, Lin SY. Progressive steps of polymorphic transformation of gabapentin polymorphs studied by hot-stage FTIR microspectroscopy. J Pharm Pharm Sci. 2010;13(1):67–77.
Reddy LS, Bethune SJ, Kampf JW, Rodríguez-Hornedo N. Cocrystals and salts of gabapentin: pH dependent cocrystal stability and solubility. Cryst Growth Des. 2009;1(9):378–85.
Taylora CP, Angelottib T, Faumanc E. Pharmacology and mechanism of action of pregabalin: the calcium channel α2–δ (alpha2–delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res. 2007;73(2):137–50.
Delaney SP, Smith TM, Korter TM. Conformation versus cohesion in the relative stabilities of gabapentin polymorphs. Roval Soc Chem. 2014;4:855–64.
Braga D, Grepioni F, Maini L, Brescello R, Cotarca L. Simple and quantitative mechanochemical preparation of the first zinc and copper complexes of the neuroleptic drug gabapentin. CrystEngComm. 2008;10(5):469–71.
Reece HA, Levendis DC. Polymorphs of gabapentin. Acta Crystallogr C. 2008;64(3):o105–8.
Lin S, Hsu C, Ke W. Solid-state transformation of different gabapentin polymorphs upon milling and co-milling. Int J Pharmaceut. 2010;396(1–2):83–90.
Tinmanee R, Larsen SC, Morris KR, Kirsch LE. Quantification of gabapentin polymorphs in gabapentin/excipient mixtures using solid state 13 C NMR spectroscopy and X-ray powder diffraction. J Pharmaceut Biomed. 2017;146:29–36.
Tinmanee R, Stamatis SD, Ueyama E, Morris KR, Kirsch LE. Polymorphic and covalent transformations of gabapentin in binary excipient mixtures after milling-induced stress. Pharm Res-Dordr. 2018:35–9.
Zong Z, Qiu J, Tinmanee R, Kirsch LE. Kinetic model for solid-state degradation of gabapentin. J Pharm Sci-US. 2012;101(6):2123–33.
Potschka H, Feuerstein TJ, Löscher W. Gabapentin-lactam, a close analogue of the anticonvulsant gabapentin, exerts convulsant activity in amygdala kindled rats. Naunyn Schmiedeberg's Arch Pharmacol. 2000;361(2):200–5.
Jehle T, Feuerstein TJ, Lagrèze WA. The effect of gabapentin and gabapentin-lactam on retinal ganglion cell survival. Situation after acute retinal ischemia in animal models. Europe PMC. 2001;98(3):237–41.
Hsu C, Lin S. Rapid examination of the kinetic process of intramolecular lactamization of gabapentin using DSC–FTIR. Thermochim Acta. 2009;486(1–2):5–10.
Zucker B, Ludin DE, Gerds TA, Lücking CH, Landwehrmeyer GB, Feuerstein TJ. Gabapentin-lactam, but not gabapentin, reduces protein aggregates and improves motor performance in a transgenic mouse model of Huntington's disease. Naunyn Schmiedeberg's Arch Pharmacol. 2004;270(2):131–9.
SH Q, invento Stable pharmaceutical preparation of γ-aminobutyric acid derivative and preparation method. 1999 1999-05-10.
Chakravarty P, Lubach JW, Hau J, Nagapudi K. A rational approach towards development of amorphous solid dispersions: experimental and computational techniques. Int J Pharmaceut. 2017;519(1–2):44–57.
Zhao Q, Miriyala N, Su Y, Chen W, Gao X, Shao L, et al. Computer-aided formulation design for a highly soluble lutein–cyclodextrin multiple-component delivery system. Mol Pharmaceut. 2018;15(4):1664–73.
Ouyang D, Smith SC. Application of molecular modeling in drug delivery. Computational Pharmaceutics. Hoboken: Wiley; 2015. p. 1–4.
Ramezanpour M, Leung SSW, Delgado-Magnero KH, Bashe BYM, Thewalt J, Tieleman DP. Computational and experimental approaches for investigating nanoparticle-based drug delivery systems. Biochim Biophys Acta Biomembr. 2016;1858(7):1688–709.
Ouyang D. Investigating the molecular structures of solid dispersions by the simulated annealing method. Chem Phys Lett. 2012;554:177–84.
Chen W, Ouyang D. Investigation of molecular dissolution mechanism of ketoprofen binary and ternary solid dispersions by molecular dynamics simulations. Mol Simul. 2017;43:1074–80.
Zhang Q, Jiang L, Mei X. Thermodynamic and kinetic investigation of agomelatine polymorph transformation. Pharm Dev Technol. 2016;2(21):196–203.
Frisch M J TGWS. Gaussian 09. Revision D.02. 2009.
Li G, Wang D, Huang Z. Crystalline interface phase study. J Synth Cryst. 2001;2(30):171–7.
Liu XY, Boek ES, Briels WJ. Prediction of crystal growth morphology based on structural analysis of the solid–fluid interface. Nature. 1995;6520(374):342–5.
Liu N, Zhou C, Shu Y, Wang B, Wang W. Molecular dynamics study on crystal morphology of N-mercaptourea dinitramide salt. Chem J Chin Univ. 2017;(12):2231–7.
André V, Fernandes A, Santos PP, Duarte MT. On the track of new multicomponent gabapentin crystal forms: synthon competition and pH stability. Cryst Growth Des. 2011;6(11):2325–34.
Jain D, Mishra M, Rani A. Synthesis and characterization of novel aminopropylated fly ash catalyst and its beneficial application in base catalyzed Knoevenagel condensation reaction. Fuel Process Technol. 2012;95:119–26.
Hamied Y, Kankan R, Rao D, ^inventors; Polymorphic forms of olanzapine. 2002 2002-02-19.
Wildfong PLD, Morley NA, Moore MD, Morris KR. Quantitative determination of polymorphic composition in intact compacts by parallel-beam X-ray powder diffractometry II-data correction for analysis of phase transformations as a function of pressure. J Pharmaceut Biomed. 2005;39(1–2):1–7.
Achrai B, Libster D, Aserin A, Garti N. Solubilization of gabapentin into HII mesophases. J Phys Chem. 2010;115(5):825–35.
Dong Z, Munson EJ, Schroeder SA, Prakash I, Grant DJW. Neotame anhydrate polymorphs II-quantitation and relative physical stability. Pharm Res-Dordr. 2002;19(9):1259–64.
Schammé B, Couvrat N, Malpeli P, Dudognon E, Delbreilh L, Dupray V, et al. Transformation of an active pharmaceutical ingredient upon high-energy milling—a process-induced disorder in Biclotymol. Int J Pharmaceut. 2016;499(1–2):67–73.
Calvo NL, Kaufman TS, Maggio RM. A PCA-based chemometrics-assisted ATR-FTIR approach for the classification of polymorphs of cimetidine: application to physical mixtures and tablets. J Pharmaceut Biomed. 2015;107(25):419–25.
Volpe DA, Gupta A, Ciavarella AB, Faustino PJ, Sayeed VA, Khan MA. Comparison of the stability of split and intact gabapentin tablets. Int J Pharmaceut. 2008;350(1–2):65–9.
Zhang J, Lv X. Study on the stability of gabapentin. Journal of Chemical Engineering of Chinese Universities. 2012 2012-10-15(05):800–5.
Sun H, Ren P, Fried JR. The COMPASS force field: parameterization and validation for phosphazenes. Comput Theor Polym Sci. 1998;1–2(8):229–46.
Bunte SW. Molecular modeling of energetic materials: the parameterization and validation of nitrate esters in the COMPASS force field. J Phys Chem B. 2000;11(104):235–65.
Ibers JA. Gabapentin and gabapentin monohydrate. Acta Cryst. 2001;C57:641–3.
Tokmakoff A, Lang MJ, Jordanides XJ, Fleming GR. The intermolecular interaction mechanisms in liquid CS2 at 295 and 165 K probed with two-dimensional Raman spectroscopy. Chem Phys. 1998;233(2):231–42.
Mogi I, Kamiko M. Striking effects of magnetic field on the growth morphology of electrochemical deposits. J Cryst Growth. 1996;166(1–4):276–80.
Braga D, Grepioni F, Maini L, Rubini K, Polito M, Brescello R, et al. Polymorphic gabapentin: thermal behaviour, reactivity and interconversion of forms in solution and solid-state. New J Chem. 2008;10:1645–808.
Ehtezazi T, Govender T, Stolnik S. Hydrogen bonding and electrostatic interaction contributions to the interaction of a cationic drug with polyaspartic acid. Pharm Res-Dordr. 2000;17(7):871–8.
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This work was supported by Shanghai Science and Technology Commission R&D Platform Special (18DZ2290500).
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Wang, J., Yang, L., Li, D. et al. Investigating the Mechanism of l-Valine in Improving the Stability of Gabapentin Combining Chemical Analysis Experiments with Computational Pharmacy. AAPS PharmSciTech 20, 114 (2019). https://doi.org/10.1208/s12249-019-1312-4
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DOI: https://doi.org/10.1208/s12249-019-1312-4