Open Pharmaceutical Sciences Journal




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ISSN: 1874-8449 ― Volume 6, 2019

Analytical Methods for Determination of Muscle Relax-ant Thiocolchicoside in Pharmaceutical Preparations- A Review



J.K. Rajput, P.H. Patil, S. J. Surana, A. A. Shirkhedkar*
Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dist. Dhule (MS), 425 405 India

Abstract

Thiocolchicoside is a centrally acting muscle relaxant and used in combination with many NSAIDs for the treatment of various musculoskeletal disorders. As it is less sedative than other centrally acting muscle relaxants hence frequently prescribed for low back pain (LBP), orthopedic, traumatic and rheumatologic disorders. It is available in market in single component and as multicomponent formulations. Various analytical methods are available for determination of thiocolchico-side in drug substances and formulated products. The present article summarizes more than 100 analytical methods including all types of chromatographic, UV-Visible spectrophotometry and radio immune assays with their percentage of utility for de-termination of thiocolchicoside in biological matrices, bulk material and different pharmaceutical formulations.

Keywords: Analytical methods, thiocolchicoside..


Article Information


Identifiers and Pagination:

Year: 2015
Volume: 2
First Page: 43
Last Page: 55
Publisher Id: PHARMSCI-2-43
DOI: 10.2174/1874844901502010043

Article History:

Received Date: 15/5/2015
Revision Received Date: 1/8/2015
Acceptance Date: 29/9/2015
Electronic publication date: 8/12/2015
Collection year: 2015

© Rajput et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the (https://creativecommons.org/licenses/by/4.0/legalcode), which permits unrestricted, noncommercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at the Department of Pharmaceuti-cal Chemistry, R. C. Patel Institute of Pharmaceutical Education and Re-search, Shirpur, Dist. Dhule (MS), 425 405, India; Tel: +91-9823691502; Fax: +91-2563251808; E-mail: shirkhedkar@gmail.com




INTRODUCTION

Thiocolchicoside (THC) is a semisynthetic derivative of cholchicoside (natural compound) which is obtained from the seeds of Gloriosa superb and Colchicum autumnale. It is an analogue of colchicines, as they share the same benzo (alpha) heptalenic moiety [1Jana S, Shekhawat GS. Critical review on medicinally potent plant species: Gloriosa superba. Fitoterapia 2011; 82(3): 293-301.
[http://dx.doi.org/10.1016/j.fitote.2010.11.008] [PMID: 21059382]
]. It is used as muscle relaxant for the treatment of painful muscle contractions in acute and chronic rheumatic conditions, in traumatology and in patients with acute low back pain [2Trellua M, Filali-Ansary A, Francon D, Adam R, Luel PL. New metabolic and pharmacokinetic characteristics of THC and its active metabolite in healthy humans. Fund Clin Pharm 2004; 18: 493-501.
[http://dx.doi.org/10.1111/j.1472-8206.2004.00277.x]
]. Moreover, Anti-inflammatory and analgesic effects of this drug have also been reported in animal models [3Janbroers JM. Review of the toxicology, pharmacodynamics and pharmacokinetics of THC, a GABA-agonist muscle relaxant with anti-inflammatory and analgesic actions. Acta Ther 1987; 13: 221-7.]. It is used since several years in the European countries, but in India the first formulation containing thiocolchicoside was approved in the year 2008 [42008.]. THC is available in combination therapy with many NSAIDs for treatment of acute low back pain and painful muscle spasms.

CHEMISTRY

Thiocolchicoside (THC) (Fig. 1) is a 2-Glucoside analog of Thiocolchicine and known as 2-demethoxy-2- glucosidoxy thiocolchicine. The Molecular formula is C27H33NO10S; and molecular weight is 563.62 g it occurs as yellow crystalline powder and is soluble in water, methanol, 0.1N HCl, 0.1N NaOH. It contains not less than 98.0 per cent and not more than 102.0 per cent of C27H33NO10S. Thiocolchicine is chemically, N-(7S)-5,6,7,9-Tetrahydro-1,2,3-trimethoxy-10-(methylthio)-9-oxabenzoa heptalen-7-yl acetamide and its semi-synthetic derivative THC is, N-(7S)-2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy)-5,6, 7,9-Tetrahydro-1,3-dimethoxy-10-(methylthio)-9-oxabenzo aheptalen-7-ylacetamide [5The Merck Index. 14th ed. Merck and Co. Inc 2009.].

Fig. (1)

Chemical structure of thiocolchicoside.



Fig. (2)

Different analytical methods employed for determination of thiocolchicoside.



Fig. (3)

Diluents used for the analysis of THC in different analytical methods.



Table 1

Spectrophotometric methods used for determination of thiocolchicoside alone and in combined dosage form.




Table 2

HPLC methods for Thiocolchicoside.




Table 3

HPLC chromatographic columns and optimized analytical parameters.




Table 4

HPTLC methods for determination of thiocolchicoside.




Table 5

Stability-indicating HPLC and HPTLC methods for determination of thiocolchicoside.




PHARMACOLOGY

Mechanism of Action

THC is a centrally acting Non-benzodiazepine muscle relaxant. It acts as a weak postsynaptic GABA agonist [6Carta M, Murru L, Botta P, et al. The muscle relaxant thiocolchicoside is an antagonist of GABAA receptor function in the central nervous system. Neuropharmacology 2006; 51(4): 805-15.
[http://dx.doi.org/10.1016/j.neuropharm.2006.05.023] [PMID: 16806306]
]. TCC has been used clinically for more than 35 years as a muscle-relaxant, anti-inflammatory, and analgesic drug, but its molecular targets and mechanisms of action are still under investigation. This compound has been shown to inhibit the binding of [3H] GABA (g-aminobutyric acid) or [3H] strychnine to rat cerebro-cortical or spinal cord membranes, respectively, in vitro as well as to corresponding autoradiographic sections in vivo. Moreover, TCC was shown to interact preferentially with a subpopulation of GABA-ARs with low-affinity binding sites for GABA. Although its precise mechanisms of action remain unknown, TCC has been thought to act as a GABA-AR agonist that induces depression of the central nervous system and, in turn, myorelaxation [7Kamath A. Thiocolchicoside: a review DHR Int J Med Sci 2013; 4(2): Available online: http://wwwdoublehelixresearchcom/ DHRIJMS 2013.].

Pharmacokinetics

On IM administration THC shows Cmax values of 113 ng/mL (4 mg dose) and 175 ng/mL (8 mg dose) in 30 min. After oral administration, no THC is detected in plasma. Only two metabolites were observed with maximum plasma concentrations one hour after THC administration [8Thiocolchicoside – Amended product information Accessed 05 Nov 2014 wwwemaeuropaeu/docs/en/Thiocolchicoside/ WC500155449pdf ].

Dosage Forms and Recommended Dose

Oral, parenteral and topical formulations of THC are available in India. The maximum recommended oral dose is 8 mg every 12 hours for not more than 7 consecutive days. The maximum intramuscular dose should be 4 mg every 12 hours, for up to 5 days [8Thiocolchicoside – Amended product information Accessed 05 Nov 2014 wwwemaeuropaeu/docs/en/Thiocolchicoside/ WC500155449pdf ].

Contraindications

THC is contraindicated in patients hypersensitive to the active substance, during the entire pregnancy period, during lactation and in women of childbearing potential not using contraception. The drug is also contraindicated in children less than 16 years of age [8Thiocolchicoside – Amended product information Accessed 05 Nov 2014 wwwemaeuropaeu/docs/en/Thiocolchicoside/ WC500155449pdf , 9European Medicines Agency recommends restricting use of thio-colchicoside by mouth or injectionEMA/706409/2013 Available at: wwwemaeuropaeu/docs/en_GB/document_library/Press_ re-lease/2013/11/WC500155448pdf 2013.].

Adverse Effects

THC has shown some side effects like anaphylactic reactions, such as pruritus, urticaria, angioneurotic oedema; anaphylactic shock following intramuscular injection, somnolence, vasovagal syncope, usually occurring in minutes following the intramuscular injection; diarrhea, gastralgia, nausea, vomiting and allergic skin reaction and phototoxicity.

On 21st November 2013, the European Medicines Agency’s Committee on Human Medicinal Product recommended that the authorized uses for THC containing medicines for use by mouth or injection should be restricted across the European Union. In addition, the dose of thiocolchicoside by mouth or injection should be restricted [8Thiocolchicoside – Amended product information Accessed 05 Nov 2014 wwwemaeuropaeu/docs/en/Thiocolchicoside/ WC500155449pdf ].

Thiocolchicoside given at doses of 6–12 mg/kg is unable to induce, in intact rats, any electrical or behavioural paroxysmal activity. However, when this compound is applied topically to the pia, given by microinjection to cerebral cortex, or administered parenterally at doses of 6 mg/kg to rats with minimal lesions of the dura and arachnoid membranes, it displays within a few minutes, a powerful convulsant activity. It is also reported that thiocolchicoside presented seizures in a patient when treated with a much lower dose (0.25 mg/kg for the cumulative dose or 0.05 mg/kg for a single dose) [10Sechi G, De Riu P, Mameli O, Deiana GA, Cocco GA, Rosati G. Focal and secondarily generalised convulsive status epilepticus induced by thiocolchicoside in the rat. Seizure 2003; 12(7): 508-15.
[http://dx.doi.org/10.1016/S1059-1311(03)00053-0] [PMID: 12967581]
, 11Giavina-Bianchi P, Giavina-Bianchi M, Tanno LK, Ensina LF, Motta AA, Kalil J. Epileptic seizure after treatment with thiocolchicoside. Ther Clin Risk Manag 2009; 5(3): 635-7.
[http://dx.doi.org/10.2147/TCRM.S4823] [PMID: 19707540]
].

Recent Safety Alerts for Thiocolchicoside

The review of thiocolchicoside was triggered by the Italian medicines regulatory agency, AIFA, following new experimental evidence which suggested that THC was broken down in the body into a metabolite called M2 or SL59.0955 that could damage dividing cells, resulting in aneuploidy (an abnormal number or arrangement of chromosomes) [9European Medicines Agency recommends restricting use of thio-colchicoside by mouth or injectionEMA/706409/2013 Available at: wwwemaeuropaeu/docs/en_GB/document_library/Press_ re-lease/2013/11/WC500155448pdf 2013.].

ANALYTICAL METHODS FOR DETERMINATION OF THIOCOLCHICOSIDE

The analysis of pharmaceuticals is an integral part of drug development process. From many years; analytical techniques like UV/Vis-Spectrophotometry, Spectrofluorimetry, Atomic Absorption Spectrometry, Capillary-Electrophoresis, Liquid-chromatography, Gas-chromatography Mass-spectrometry, Luminescence, Voltammetry and Polarography have been studied for the analysis of pharmaceutical compounds. Amongst all these methods, chromatographic methods have been widely exploited and preferred over other methods [12Siddiqui MR, Al Othman ZA, Rahman N. Analytical techniques in pharmaceutical analysis: a review 2013.
[http://dx.doi.org/10.1016/j.arabjc.2013.04.016]
]. THC is a commonly used muscle relaxant in the treatment of acute painful muscle spasms. It is available in combined treatment with many non-steroidal anti-inflammatory drugs (NSAIDs) like Aceclofenac, Diclofenac, Paracetamol, Ketoprofen, Etodolac, Etoricoxib, Lornoxicam and Floctafenine and the literature reports vast number of analytical methods such as UV-spectrophotometry, HPLC, TLC-densitometry and LC-MS/MS for the determination of THC in biological matrices, bulk material and the corresponding pharmaceutical formulations.

Consequently, the objective of the present review is to compile the analytical methods published so far for estimation of THC in biological samples including metabolites and degradants, bulk materials and pharmaceutical formulations. The percentage utility of these techniques is calculated and shown in Fig. (2), from which it can be noticed that High-Performance Liquid Chromatography (HPLC) and Spectrophotometric methods have been most extensively used. Apart from this, the present review will be useful for selecting the diluents Fig. (3) and the analytical procedure for the assay of THC with different concentrations ranges, selective accuracy and precision in various biological material or pharmaceuticals.

Spectrophotometry [13Acharjya SK, Mallick P, Panda P, Annapurna MM. Spectrophotometric methods for the determination of thiocolchicoside in bulk and pharmaceutical dosage form. J Pharm Edu Res 2010; 1(1): 51-7.-29Hapse SA, Thorave RR, Kadaskar PT, Shirsath AS, Dokhe DM. Novel spectrophotomeric method for simultaneous estimation & validation of paracetamol, thiocolchicoside and aceclofenac in tablet dosage form by UV spectrophotometer. J Pharm Res 2011; 4(11): 3928-9.] and Spectrofluorimetry [30Nikhade RD, Thakur AD, Choudhari SB, Chandewar AV. Simultaneous estimation of paracetamol, thiocolchicoside and aceclofenac by uv spectrophotometer using multicomponent mode method. J Pharm Res 2011; 4(7): 2297-9.]

In the literature, nearly twenty seven UV- Spectrophotometric methods have been reported so far for estimation of THC alone and in combined dosage forms as well as a single Spectrofluorimetry method has been also established for THC from injection. Table 1 illustrates the summary of the reported UV-Spectrophotometric and Spectrofluorimetry methods indicating the basic principle, matric used, λmax, solvent and linearity range.

Methods for Analysis as a Single Component

Eight methods for estimation of THC in a capsule dosage form as a single component have been developed. The first, second and third method employ first order, second order and third order derivative spectroscopy to reduce spectral interference. The fourth method employs selection of area under curve in wavelength region of 254 – 264 nm using 0.1 N Sodium hydroxide solution prepared in double distilled water [13Acharjya SK, Mallick P, Panda P, Annapurna MM. Spectrophotometric methods for the determination of thiocolchicoside in bulk and pharmaceutical dosage form. J Pharm Edu Res 2010; 1(1): 51-7.]. Two simple and sensitive spectrophotometric methods have been developed for the quantitative estimation of THC from its capsule formulation. The first method is a zero order UV spectrophotometric method using distilled water as solvent; the drug showed absorption maximum at 259.8 nm and linearity was observed in the concentration range of 5.0 – 50 µg/mL. The second method is area under curve selecting the wavelength range of 269.8 - 249.8 nm [14Joshi RR, Gupta KR. UV-spectrophotometric determination of thiocolchicoside in capsule. Der Pharm Chem 2010; 2(2): 384-91.]. In other method, utilizing UV-Spectrophotometric procedure, based on the linear relationship between the THC concentration and the λmax amplitude at 279 nm [15Bhandari A, Nawal M, Jathalia R, Bhandari M, Solanki R, Nagori BP. UV spectrophotometric etermination of thiocolchicoside from capsule dosage form. J Pharm Res 2011; 4(12): 4685-7.].

Methods for Analysis in Combined Dosage form with Other Drugs

As THC is available with many NSAIDS, analgesics and antipyretics in combined pharmaceutical formulations; literature revealed range of UV-Spectrophotometric methods for simultaneous determination of THC in combined dosage forms.

Two simple, rapid, accurate and economical methods have been developed for the estimation of THC and DCF-P in capsules. The first method; involves formation of Q-absorbance equation at 264 (isoabsorptive point) and at 259 nm, while the second method; involves formation of simultaneous equation at 259 and 271 nm, using water as solvent [16Suganthi A, Ravi TK. Development of validated spectrofluorimetric method for the estimation of thiocolchicoside. Int J ChemTech Res 2012; 4(4): 1674-80.].

Two methods; absorption correction and area under curve have been established for the quantitative estimation of THC and DCF-P from tablet formulation using methanol as a solvent. In absorption correction method, quantitative estimation of THC was carried out by subtracting interference of diclofenac using experimentally calculated absorption factor, also Beer’s plot was constructed for DCFP and THC in solution mixture at different concentration (25:4, 37.5:6, 50:8, 62.5:10, 75:12 µg/mL) levels. For the simultaneous equations using area under curve; 252.56 - 260.59 nm (λ1 - λ2) and 278.51 - 285.53 nm (λ3 - λ4) have been selected as a sampling wavelength ranges for estimation of DCFP and THC [17Umarkar AR, Bagad YM, Rewatkar NS, Thote LT. Simultaneous spectrophotometric estimation of thiocolchicoside and diclofenac potassium in combined capsule dosage form. Asian J Res Chem 2011; 4(3): 370-2.].

Two methods for simultaneous determination of DCFP with THC in combined dosage form have been developed. The first method is based on first derivative of the ratio spectra (1DD) measuring the amplitudes at 268.78 nm and 355.62 nm. For the second method, two wavelengths were selected for each drug in a way so that the difference in absorbance is zero for another drug [18Choudhari VP, Chabukswar AR, Savakhande SN, Tryambake MU, Suryawanshi V, Smsayal PK. Simultaneous spectrophotometric estimation of thiocolchicoside and diclofenac potassium in combined dosage form by ratio derivative and dual wavelength method. Int J Curr Res Rev 2010; 2(12): 3-10.]. A simple method employed the formation and solving of simultaneous equation using 259 nm and 277 nm as the wavelength for forming equation has been also developed for DCFP with THC using 0.1 N NaOH as a solvent [19Choudhari VP, Chabukswar AR, Mangesh UT, Sachin NS. Spectrophotometric simultaneous determination of diclofenac potassium B.P. and thiocolchicoside in combined tablet dosage form by absorption corrected method and area under curve method. Int J Pharm Sci Rev Res 2011; 7(2): 182-5.]. A single method, using multicomponent mode of analysis of the instrument is used for the simultaneous estimation of the two drugs THC and DCF-P respectively [20Vilas D, Patil RY. Chaudhari spectrophotometric method for estimation of thiocolchicoside and diclofenac potassium in capsule dosage form by simultaneous equation method. Int J Drug Discov Herb Res 2012; 2(2): 410-2. [IJDDHR].]. Three spectrophotometric methods (A–C) were described for simultaneous determination of THC with DCF-S in capsule formulation. The first ‘method A’ is absorbance correction method and determines concentration of DCFS directly from calibration plot by measuring absorbance at 276.6 nm and THC was determined after correction for absorbance of DCF-S at 372.8 nm. The second method is based on first order derivative spectroscopy to overcome spectral interference from other drug and wavelengths 278.6 nm and 243.2 nm were selected for the determination of the DCFS and THC, respectively. In the third method, diclofenac sodium was determined by plotting the difference in absorbance at 244 and 269 nm (difference is zero for THC) against the concentration of DCFS. Similarly for the determination of THC, the difference in absorbance at 266.8nm and 290 nm (difference is zero for DCFS) was plotted against the concentration of DCFS [21Umarkar AR, Rewatkar NS, Charde MS, Charde RM. Simultaneous estimation of thiocolchicoside and diclofenac potassium by uv spectrophotometer using multicomponent method. Int J Chem Tech Res 2011; 3(2): 944-7.].

Two methods for simultaneous estimation of THC and DCFP in combined dosage form have been described. In the first method; the wavelengths 276.5 nm (λmax of DCFP) and

373.0 nm (where DCFP does not interfere in absorbance of THC) were selected for analysis by proposed method, while the second method; involves formation of simultaneous equation at 260 and 275.5 nm, using 0.1 N NaOH as solvent [22Sengar MR, Gandhi SV, Patil UP, Rajmane VS. Simultaneous determination of diclofenac sodium and thiocolchicoside in fixed dose combination by spectrophotometry. Asian J Pharm Clin Res 2010; 3(2): 89-91.].

A simple UV-Spectrophotometric absorption correction method has been reported, which is based upon determination of THC at 397.80 nm and DCF-P at 271.0 nm, in distilled water [23Joshi RR, Gupta KR. Simultaneous UV-spectrophotometric determination of thiocolchicoside and diclofenac in pharmaceutical formulation. Der Pharm Sin 2010; 1(2): 44-51.].

Only one AUC method is available for simultaneous analysis of THC with ACE. The method employed selection of area under curve in wavelength region of 264.5 - 254.5 nm for THC; 279.0 - 269.0 nm for Aceclofenac and solving the equations [24Umarkar AR, Bagad YM, Bhurat MR, Kawatikwar PS. Absorption correction method for estimation of thiocolchicoside and diclofenac potassium in combined capsule dosage form. Int J Pharm Sci 2011; 3(1): 1046-9.].

An absorbance ratio (Q-analysis) UV spectrophotometric method has been developed for the simultaneous determination of THC and ETD from the combined tablet dosage form using 232nm as isoabsorptive point and 0.1 N HCl as solvent [25Chitlange SS, Shinde PS, Pawbake GR, Wankhede SB. Simultaneous estimation of thiocolchicoside and aceclofenac in pharmaceutical dosage form by spectrophotometric and LC method. Der Pharm Lett 2010; 2(2): 86-93.]. Two methods, i.e. Absorbance correction and First order derivative spectroscopy are also reported for simultaneous estimation of THC with DXKET using methanol as solvent. The amount of drug determined by proposed methods ranges from 99.8 to 100.2 % for both. The method reports recovery study values of THC and DXKET 99.8% and 100.2%, respectively for both the methods with RSD less than 2 %. [26Thankappan S, Parmar A, Sailor B, Vekariya K, Shah D. Simultaneous estimation of etodolac and thiocolchicoside by uv spectrophotometric method in tablet formulation. Int J Pharm Innov 2012; 2(2): 192-200.] Few other methods, First order derivative spectroscopic (% label claimed 99.94 % for THC and 99.60 % for KET) and Absorbance correction method (% label claimed 100.32 % for THC and 99.95 % for KET) is presented in literature for estimation of THC with KET using distilled water as solvent [27Harde MT, Dharam DL, Jadhav SB, Balap AR. Development and validation of rp-hplc method for simultaneous estimation of thiocolchicoside and dexketoprofen in bulk and tablet dosage form. Int J Pharm Tech Res 2012; 4(4): 1797-802.]. Two methods using multicomponent mode of analysis are also reported for THC in combined dosage form with PCM and ACE. The accuracy of the both methods was evaluated by percentage recovery (by standard addition method) of all three drugs and it was in the range of 99.84 - 101 % with values for SD and % RSD of < 2% [28Wankhede SB, Zambare SS, Chitlange SS. Estimation of thiocolchicoside and ketoprofen in pharmaceutical dosage form by spectrophotometric methods. J Pharm Res 2010; 3(4): 707-10., 29Hapse SA, Thorave RR, Kadaskar PT, Shirsath AS, Dokhe DM. Novel spectrophotomeric method for simultaneous estimation & validation of paracetamol, thiocolchicoside and aceclofenac in tablet dosage form by UV spectrophotometer. J Pharm Res 2011; 4(11): 3928-9.].

A single Spectroflurometric method was reported for estimation THC in injection which is based on the oxidation of THC with cerium (IV) to produce cerium (III), whose fluorescence was monitored at 366 nm [30Nikhade RD, Thakur AD, Choudhari SB, Chandewar AV. Simultaneous estimation of paracetamol, thiocolchicoside and aceclofenac by uv spectrophotometer using multicomponent mode method. J Pharm Res 2011; 4(7): 2297-9.].

Chromatography

High-Performance Liquid-Chromatography (HPLC) [31Walash M, Belal F, Eid M, el-Abass SA. Simultaneous HPLC determination of thiocolchicoside and glafenine as well as thiocolchicoside and floctafenine in their combined dosage forms. J Chromatogr Sci 2011; 49(2): 159-64.
[http://dx.doi.org/10.1093/chrsci/49.2.159] [PMID: 21223643]
-54Rele RV, Mali RN. Advance simultaneous determination of paracetamol, thiocolchicoside and aceclofenac in tablets by reverse phase high performance liquid chromatography. Der Pharm Sin 2014; 5(1): 34-9.]

About Twenty four HPLC methods were reported for determination THC in combined pharmaceutical formulations. Table 2. shows the summary of the reported HPLC methods indicating the mobile phase used for determination, sample matric, λmax and linearity (r2).

Table 3. Summarizes the column with specifications for analysis by HPLC methods along with the conditions used such as flow rate, temperature, detector, analysis type etc.

High-Performance Thin-layer Chromatography [55Gandhi S, Deshpande P, Sengar M. High performance thin layer chromatographic determination of diclofenac sodium and thiococlhicoside in fixed dose combination. Int Res J Pharm 2010; 1(1): 220-4.-63Rajmane VS, Gandhi SV, Patil UP, Sengar MR. High-performance thin-layer chromatographic determination of etoricoxib and thiocolchicoside in combined tablet dosage form. J AOAC Int 2010; 93(3): 783-6.
[PMID: 20629376]
]

Nine simple HPTLC methods have been reported for simultaneous estimation of THC in combined dosage form with ACE, DCF, DXKET, LOR, ETR and ETD. Table 4. shows the summary of the reported HPTLC methods.

Estimation of THC Using Hyphenated Techniques and in Biological Matrices

In Hyphenated techniques, Liquid-chromatography (LC), Gas-chromatography (GC) or capillary electrophoresis is linked to spectroscopic techniques, e.g. MS, FT-IR, NMR etc. resulting in new advanced techniques like CE-MS, GC-MS, MS-MS, LC-MS LC-MS-MS LC-NMR etc. Such techniques provide structural information and identification of drugs and degradation compounds. Amongst these analytical techniques, LC-MS is reported to be extensively used technique. An LC-ESI–MSn analysis is performed for forced degradation study of THC to assess its inherent chemical stability. Method reports five degradation products of THC and the degradants were characterized by MS, NMR and IR spectroscopic techniques confirming it by synthesis of degradants. The study elucidated that hydrolysis and oxidation are major degradation pathways for THC. Five degradation products were resulted and the DPs were:D1SO-(N-1,2-dimethoxy-10-methyl sulphoxide-9-oxo-3-(3,4,5-trihydroxy-6 hydroxymethyl- tetrahydropyran-2-yloxy)-5,6,7,9-tetrahydro-benzoa heptalen-7-yl-acetamide), D1SO2-(N-1,2-dimethoxy-10-methylsulphone-9-oxo-3-(3,4,5-trihydroxy-6-hydroxymethy-ltetrahydropyran-2-yloxy)-5,6,7,9-tetrahydro-benzoaheptalen- 7-yl-acetamide), D2(1,2-dimethoxy-10-methylsulphanyl-9-oxo-3-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy)-5,6,7,9-tetrahydro-benzoaheptalen-7-yl-amine), D3 (N-1,2-dimethoxy-3-hydroxy-10-methylsulphanyl-9-oxo-5,6,7,9-tetrahydro-benzoaheptalen-7-yl-acetamide or 3-O-demethylthiocolchicine), D4 (1,2-dimethoxy-3-hydroxy-10-methylsulphanyl-9-oxo-5,6,7,9-tetrahydro-benzo aheptalen-7-yl-amine or N-deacetyl-3-O-demethy-lthiocochicine). Products D1SO and D3 could be considered as the indicators of THC stability and they will be introduced in the development and validation of HPLC–UV stability-indicating methods for determination of THC in drug substance and drug product [64Erika G, Silvio A, Giorgio G. Forced degradation study of thiocolchicoside: characterization of its degradation products. J Pharm Biomed Anal 2012; 61: 215-23.
[http://dx.doi.org/10.1016/j.jpba.2011.12.008] [PMID: 22226415]
].

Quantitative determination of drugs and their metabolites from biological matrices such as blood, plasma, serum, or urine play vital role in drug discovery and development. Chromatographic methods like HPLC or GC have been widely used for the bioanalysis of small molecules and Liquid-Chromatography coupled with Triple Quadrupole Mass Spectrometry (LC/MS/MS) is the single most commonly used technology amongst it. A highly sensitive Liquid-Chromatography–tandem Mass Spectrometry (LC-MS-MS) method has been illustrated for the determination of 3-desmethylthiocolchicine in human plasma to evaluate the bioequivalence of thiocolchicoside after oral administration. The study divulge that thiocolchicoside is rapidly converted to 3-desmethylthiocolchicine (possibly partially in the acidic stomach juices) during absorption and during the first-pass effect through the liver [65Sutherland FC, Smit MJ, Herbst L, et al. Highly specific and sensitive liquid chromatography-tandem mass spectrometry method for the determination of 3-desmethylthiocolchicine in human plasma as analyte for the assessment of bioequivalence after oral administration of thiocolchicoside. J Chromatogr A 2002; 949(1-2): 71-7.
[http://dx.doi.org/10.1016/S0021-9673(02)00008-0] [PMID: 11999759]
]. A radioimmunoassay technique is also reported in literature to study the single-dose bioavailability of thiocolchicoside by oral and intramuscular route. This method report to relative bioavailability of both oral formulations was approximately 25%, compared to the intramuscular formulation. An another study based on radioimmunoassay using cross-reacting colchicines- specific polyclonal antibodies and 3H colchicines as marker is also depicted. In the study cross-reactivity tests were performed for some colchicine analogues, but not for

3-desmethyl thiocolchicine (aglycone part of thiocolchicoside) [66Sandouk P, Bouvier d’Yvoire M, Chretien P, Tillement JP, Scherrmann JM. Single-dose bioavailability of oral and intramuscular thiocolchicoside in healthy volunteers. Biopharm Drug Dispos 1994; 15(1): 87-92.
[http://dx.doi.org/10.1002/bdd.2510150108] [PMID: 8161719]
]. Similarly, a capillary gas chromatography-mass spectrometry (GC-MS) method is presented for THC following enzymatic hydrolysis of thiocolchicoside to its aglycone (3-demethylthiocolchicine). The study reports oral bioavailability of the capsule formulation was 1.06 +/- 0.39 relative to the tablet formulation [67Perucca E, Poitou P, Pifferi G. Comparative pharmacokinetics and bioavailability of two oral formulations of thiocolchicoside, a GABA-mimetic muscle relaxant drug, in normal volunteers. Eur J Drug Metab Pharmacokinet 1995; 20(4): 301-5.
[http://dx.doi.org/10.1007/BF03190249] [PMID: 8983937]
].

A bioequivalence study has been reported for fixed dose combination of thiocolchicoside and lornoxicam in twenty four healthy male volunteers using liquid chromatography–tandem mass spectrometry (LC-MS-MS) method [68Agarwal S, Das A, Chowhury HR, Sarkar AK, Chattaraj TK, Pal TK. Bioequivalence study of fixed dose combination tablet containing lornoxicam and thiocolchicoside in healthy subjects. Int J Pharm Sci Res 2011; 2(10): 2718-23.]. Similarly, a bioanalytical method is also reported for simultaneous determination of THC and lornoxicam from pharmaceutical formulation in human plasma which uses an isocratic RP-HPLC method [69Kumar P, Shukla S, Subudhia BB, Ganure AL. Bioanalytical method development and validation for the simultaneous estimation of thiocolchicoside and lornoxicam in human plasma and in pharmaceutical dosage form by RP-HPLC. Int J Pharm Pharm Sci 2012; 4(3): 252-9.].

A bioanalytical method for the simultaneous estimation of active metabolite of thiocolchicoside (3-demythylthiocolchicine) and diclofenac in human plasma by means of LC-MS/MS is also reported. The method employed Reversed-Phase phenomenex gemini C18 column with a mobile phase containing Methanol: Water (containing 0.2% formic acid) (9:1, v/v). The calibration curves were linear over the range of 1 to 50 ng/mL for 3-demythylthiocolchicine and 25 to 2500 ng/mL for DCF with the lower limit of quantification validated at 0.5 ng/mL for 3-demythylthiocolchicine and 5 ng/mL for DCF [70Tapan KP. Bioanalytical method development and validation for the simultaneous estimation of active metabolite thiocolchicoside and diclofenac in human plasma by LCMS/MS with a special emphasis to bioequivalence study. J Bioequivalence Bioavailab 2013; 5(3): 112.].

One UV-spectrophotometric method was found for simultaneous estimation of THC with ETD using methanol as solvent by simultaneous equation and Q-absorbance ratio method in tablets and in spiked human urine. The authors have also performed force degradation study for both drugs and reported that THC is only subjected to alkaline hydrolysis indicating change in λmax of THC. The authors also compared their proposed method with reference method from literature and concluded that, the present method is better than the existing reference method because 0.1 N NaOH is used in reference method which can be responsible for degradation of THC in alkaline medium and interfere with the λmax of THC [71Pandey R, Patil PO, Bari SB, Dhumal DM. Simultaneous estimation of etodolac and thiocolchicoside in bulk and in tablet formulation by uv-spectrophotometry. Chem Ind Chem Eng Q 2014; 20(1): 9-17.
[http://dx.doi.org/10.2298/CICEQ120114098P]
].

Stability-Indicating Methods (SIM) for Determination of THC [72Umarkar AR, Rewatkar NS, Chaple DR, Thote LT, Chaudhari SB, Bhurat MR. Stability Indicating RP-HPLC method for estimation of thiocolchicoside in capsule dosage forms. Res J Pharm Bio Chem Sci 2011; 2(10): 750-6.-83Deshpande S, Patel AR. Stability indicating simultaneous estimation of Thiocolchicoside, Paracetamol and diclofenac sodium in bulk drug and formulation by RP-HPLC. World J Pharm Sci 2014; 2(7): 671-8.]

About thirteen stability-indicating methods have been reported for determination of THC in bulk substances and pharmaceutical formulations using different analytical techniques. Among it, three methods are for estimation of THC alone and ten of them described for stability-indicating nature of method for combined dosage form. Maximum of 14-15% were reported using HPLC, 3-4 % were based on HPTLC and 1 - 2% were LC/MS methods. Table 5. shows the reported stability-indicating methods for THC; illustrating sample matrix, λmax, linearity range and retention time/factor.

Official Methods for Analysis of Thiocolchicoside [84Indian Pharmacopeia 6th ed, Govt of India, Ministry of Health and Family Welfare, Gaziabad 2010: vol-III, pp 2213-4 2010.]

THC is official drug in Indian Pharmacopoeia 2010. Two HPLC methods are described for assay of THC from pharmaceutical formulations and its related substances.

CONCLUSION

The present review epitomizes numerous analytical methods applied for the determination of THC. A great number of studies including UV/Vis-Spectrophotometry, Spectrofluorimetry, HPLC, HPTLC, LC-ESI-MS, LC-MS, GC-MS etc. were reported for analysis of thiocolchicoside in bulk and in its combined pharmaceutical formulations as well as in plasma. It has been found that Liquid-Chromatography with UV-detection is the most studied for the determination of THC in bulk as well as pharmaceutical dosage forms while LC-MS and LC-MS/MS are the widely used for its estimation from plasma and other biological fluids to determine its pharmacokinetics as well as for bioavailability and bioequivalence studies. Few chromatographic methods like HPTLC and GC-MS are also published in literature. Certain Spectrophotometric methods in UV–Visible as well as fluorimetry are most often used for quantification of THC.

ABBREVIATIONS

ACN  =  Acetonitrile
ACE  =  Aceclofenac
CE  =  Capillary Electrophoresis
DCFS  =  Diclofenac Sodium
DCFP  =  Diclofenac Potassium
DPs  =  Degradation Products
DXKET  =  Dexketoprofen
ESI-MS  =  Electron Spray Ionization Mass Spectrometry
ETD  =  Etodolac
ETR  =  Etoricoxib
FN  =  Floctafenine
GC  =  Gas Chromatography
GC-MS  =  Gas Chromatography- Mass Spectroscopy
GF  =  Glafenine
HPLC  =  High Performance Liquid Chromatography
HPTLC  =  High Performance Thin Layer Chromatography
IM  =  Intra-muscular
IR  =  Infrared
KET  =  Ketoprofen
LBP  =  Low Back Pain
LC  =  Liquid Chromatography
LOD  =  Limit of Detection
LOQ  =  Limit of Quantitation
LOR  =  Lornoxicam
M  =  Concentration (mol/L)
MP  =  Mobile Phase
MS  =  Mass Spectrometry
nm  =  Nanometer
NMR  =  Nuclear Magnetic Resonance
NSAIDs  =  Non-Steroidal Anti-inflammatory Drugs
OPA  =  Orthophosphoric Acid
PCM  =  Paracetamol
RP-HPLC  =  Reversed Phase-High Performance Liquid Chromatography
R.S.D.  =  Relative Standard Deviation
TEA  =  Triethylamine
TFA  =  Trifluoroacetic Acid
THC  =  Thiocolchicoside
TLC  =  Thin Layer Chromatography
UV–Vis  =  Ultraviolet-Visible

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

The authors are thankful to Dr. S.J. Surana, Principal R. C. Patel Institute of Pharmaceutical Education and Research for providing necessary facilities.

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Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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