Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=batc20 Critical Reviews in Analytical Chemistry ISSN: 1040-8347 (Print) 1547-6510 (Online) Journal homepage: https://www.tandfonline.com/loi/batc20 Status of Rifaximin: A Review of Characteristics, Uses and Analytical Methods Ana Carolina Kogawa & Hérida Regina Nunes Salgado To cite this article: Ana Carolina Kogawa & Hérida Regina Nunes Salgado (2018) Status of Rifaximin: A Review of Characteristics, Uses and Analytical Methods, Critical Reviews in Analytical Chemistry, 48:6, 459-466, DOI: 10.1080/10408347.2018.1447355 To link to this article: https://doi.org/10.1080/10408347.2018.1447355 Published online: 26 Mar 2018. Submit your article to this journal Article views: 199 Citing articles: 1 View citing articles https://www.tandfonline.com/action/journalInformation?journalCode=batc20 https://www.tandfonline.com/loi/batc20 https://www.tandfonline.com/action/showCitFormats?doi=10.1080/10408347.2018.1447355 https://doi.org/10.1080/10408347.2018.1447355 https://www.tandfonline.com/action/authorSubmission?journalCode=batc20&show=instructions https://www.tandfonline.com/action/authorSubmission?journalCode=batc20&show=instructions https://www.tandfonline.com/doi/citedby/10.1080/10408347.2018.1447355#tabModule https://www.tandfonline.com/doi/citedby/10.1080/10408347.2018.1447355#tabModule Status of Rifaximin: A Review of Characteristics, Uses and Analytical Methods Ana Carolina Kogawa and H�erida Regina Nunes Salgado S~ao Paulo State University (UNESP), School of Pharmaceutical Sciences, Campus Araraquara, Araraquara, S~ao Paulo, Brazil ABSTRACT Rifaximin, an oral antimicrobial, has many advantages because it is selective intestine, has minimal adverse effects and is used for the treatment of some diseases such as hepatic encephalopathy, irritable bowel syndrome, travelers’ diarrhea, ulcerative colitis, Clostridium difficile and acute diarrhea. Rifaximin in the form of 200 mg tablets is commercially available. The crystalline a form is therapeutically safe and effective. In most of the official compendia, rifaximin has no monograph and in none of them is there a monograph for rifaximin tablets. The literature, however, contemplates this gap with varied methods. The literature presents some methods for evaluation of rifaximin in both biological fluid and pharmaceutical product. High performance liquid chromatography stands out for the evaluation of rifaximin. Most of the methods reported in the literature are for pharmaceuticals products. They use (1) toxic organic solvents, harmful to the operator and the environment, and/or (2) buffer solution, which has a shorter service life and requires time-consuming washes of the chromatographic system generating more waste. So, this work aims to discuss (i) properties; (ii) applications; (iii) polymorphism and (iv) analytical methods of rifaximin by the look of green chemistry. This review shows an extremely current topic of great importance to the chemical-pharmaceutical area and everything it involves, since the analytical process until the impact on the environment in which it is embedded. KEYWORDS Analytical methods; antimicrobial; green chemistry; HPLC; polymorphism; rifaximin Introduction Rifaximin is an oral antimicrobial with broad spectrum of action non-absorbable. It acts in the gastrointestinal tract and presents minimal adverse effects.[1,2] It is practically not absorbed and achieves high concentrations in the human intestine, where it is active against many enteropathogens.[3] It is a non-systemic antimicrobial derived from rifamycin.[4] Its high tolerability can be compared to placebo.[2,5] It is used safely for the treatment of many different diseases by children, the elderly and debilitated people. Thus, rifaximin reaches a large target audience and therefore analytical methods for the evaluation of its quality must be effective and reliable. However, in the current scenario, they must also be environmentally friendly. The use of non-toxic reagents, the careful choice of the analytical method as well as the apparatus to be used, the speed of the analysis, the residues generated and the amount of sample used are examples of parameters relevant to green chemistry. Currently, analytical processes must be viewed in a multi-dimensional way and appropriate to the world reality, where there is a growing concern with the health of the envi- ronment and everything that surrounds it.[6–9] Therefore, the objective of this review is to discuss about (i) properties, (ii) applications, (iii) polymorphism and (iv) analytical methods of rifaximin by the look of green chemistry. Rifaximin Rifaximin, Figure 1, has structure analogous to rifampicin and is a derivative of rifamycin. Rifampicin and rifabutin are equally effective in tuberculosis schemes for HIV-posi- tive and HIV-negative patients. Rifabutin is more active than rifampicin against Mycobacterium avium, and is preferentially used in multiple drug regimens for these infections, but otherwise rifampicin is the drug of choice. Resistance develops rapidly with rifampicin, so it is rarely used alone. Rifaximin binds to the b subunit of the bacterial enzyme RNA polymerase DNA-dependent and inhibits bacterial RNA synthesis.[2] Rifaximin is used in cases of hepatic encephalopathy,[1–5,10] ulcerative colitis,[10] irritable bowel syndrome,[4,2] Clostridium difficile,[2,3] diarrhea of travelers[2–4,11,12] and acute diarrhea.[13] Hepatic encephalopathy Hepatic encephalopathy is a complex liver disease. It is consid- ered as a metabolic disorder or neurophysiological.[10] Normal patients remove nitrogen residues produced by gastrointestinal bacteria. In this process, ammonia is metabo- lized in urea and excreted. Patients with hepatic encephalopa- thy cannot convert ammonia to urea and consequently it accumulates in the blood. This generates accumulation in the central nervous system and affects neurotransmission. Hepatic CONTACT H�erida Regina Nunes Salgado salgadoh@fcfar.unesp.br S~ao Paulo State University (UNESP), School of Pharmaceutical Sciences, Campus Araraquara, Rodovia Araraquara-Ja�u, km 1, 14800-903, Araraquara, S~ao Paulo, Brazil. Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/batc. ©2018 Taylor & Francis Group, LLC CRITICAL REVIEWS IN ANALYTICAL CHEMISTRY 2018, VOL. 48, NO. 6, 459–466 https://doi.org/10.1080/10408347.2018.1447355 https://crossmark.crossref.org/dialog/?doi=10.1080/10408347.2018.1447355&domain=pdf&date_stamp=2018-05-11 mailto:salgadoh@fcfar.unesp.br http://www.tandfonline.com/batc https://doi.org/10.1080/10408347.2018.1447355 http://www.tandfonline.com encephalopathy is associated with portal hypertension in patients with cirrhosis and chronic liver disease.[2] Treatment The neuropsychiatric symptoms and neuromuscular dysfunc- tion associated with hepatic encephalopathy are accounted for the clinical and socioeconomic burden of chronic liver disease for patients and their caregivers. Hepatic encephalopathy often results in hospitalization and decreased survival in patients with cirrhosis. Prevention of hepatic encephalopathy episodes can improve the results for patients while they wait for trans- plantation and improve post-transplant function. A long-term therapeutic intervention to prevent the recurrence of hepatic encephalopathy is necessary to decrease the burden of health care, enhance quality of life and improve results for patients with chronic diseases.[1] Current strategies as removal of precipitating factors, increase the elimination of ammonia or reduce ammonia pro- duction are used for hepatic encephalopathy. For this, lactulose was chosen, but its continued use is problematic and there are patients who do not tolerate or do not respond to therapy with lactulose.[1,2,5] Rifaximin has been an option for this case.[2,5] Irritable bowel syndrome Irritable bowel syndrome, a chronic gastrointestinal disease, affects up to 20% of the general population. The diagnosis is often an exclusion diagnosis.[2] It can be characterized by change in bowel habits, abdominal pain, diarrhea, constipation and swelling. The etiology of irrita- ble bowel syndrome may be due to changes in peripheral and central sensory.[2] In addition to this, data show that there is a relationship between intestinal bacterial overgrowth and irrita- ble bowel syndrome.[2,4] In it the normal intestinal flora of the proximal intestine is altered in quantity and quality; flora adopts the characteristics of large bowel flora of aerobic and anaerobic and aerobic and anaerobic coliform predominate at densities > 103 CFU mL¡1 and often greater than 105 CFU mL¡1.[4] Clostridium difficile Rifaximin can be a treatment option for patients with multiple recurrent episodes of C. difficile according to the Society for Healthcare Epidemiology of America (SHEA) and Infectious Diseases Society of America (IDSA).[2,3] Traveler’s diarrhea Traveler’s diarrhea is a disease very common for those return- ing from tropical areas and it is usually caused by Escherichia coli (enterotoxigenic and enteroaggregative mostly), which may be identified in 50% of cases,[11,12] followed by Shigella spp. The traveler’s diarrhea is a self-limited disease and normally treat- ment with antibiotics is not required, unless the circumstances become worse.[12] Treatment The most common treatment for travelers’ diarrhea with anti- biotics uses fluoroquinolones. However, amoxicillin C clavula- nate, azithromycin, erythromycin or cotrimoxazole are often used.[12] Quinolones presents a good activity against traveler’s diarrhea pathogens, but they are expensive for some coun- tries. However, currently pathogens causing travelers’ diar- rhea have been shown to be resistant to quinolones. A reduction in the effectiveness of quinolones highlights the urgency of finding alternative therapies. For example, cipro- floxacin is very effective against E. coli and Shigella sonnei, but it is associated with toxicity and drug interactions. Thus, non-absorbable antibimicrobials should overcome the limitations of the systemic antimicrobials and rifaximin, a derivative of rifamycin characterized by a broad antibacte- rial spectrum, is an excellent option.[11,12] Acute diarrhea Acute diarrhea, severe and fatal in some cases, hits children most of the time. Children with genitourinary malformations or anal dysfunctions often experience diarrhea outbreak due to modification of the normal bacterial flora.[13] Treatment Diarrhea frequently occurs in children. Some of them had expe- rience with acute gastroenteritis because they used nitrofuran- toin or trimethoprim/sulfamethoxazole to prevent urinary tract infections. Fast antimicrobial treatment of diarrhea episodes in these children is necessary to avoid complications. In this situa- tion, rifaximin is a good choice. It has a wide range of antimi- crobial activity, is selective bowel and therefore has minimal adverse effects.[13] Polymorphism Rifaximin is marketed in hydrate form, but the environmental conditions may trigger their conversion to the amorphous form.[14] On the market tablets of 200 mg are found. The dose is 600 mg (1 tablet 3 times daily) or 800 mg (2 tablets 2 times a day). Rifaximin, an antimicrobial for local action in the gastroin- testinal tract, can exist in form of crystals and amorphous. Figure 1. Chemical structure of rifaximin (CAS 80621-81-4, C43H51N3O11 and molecular weight 785.9 g mol¡1). 460 A. C. KOGAWA AND H. R. N. SALGADO Rifaximin formulation contains a form that has limited sys- temic bioavailability. However, the amorphous form was found in formulation of generic products. This does not guarantee the great tolerability of rifaximin, since the amorph form has a higher systemic bioavailability.[14] The regulatory authorities are increasingly attentive to the polymorphisms. Generic products contain the same active principle, same dose, same pharmaceutical form, administered in the same way, in the same dosage and used for the same therapeutic indication of the reference product. This context, regulatory agencies recommended guides to contemplate trials capable of recognizing the interchangeability of branded and generic products.[14–16] Therapeutic problems can exist in the administration of dif- ferent crystalline forms of products containing rifaximin, but the problem is greater when the exchange of crystalline forms and amorphous forms happens.[14] The polymorphism of drug depends of the synthesis, sol- vents used, purification and crystallization. Normally, the pro- ductive process generates a crystalline form. Studies of the literature show that the reference rifaximin has a crystalline form in the form of a hydrate and that changes in the solvents used in its process can lead to a mixture of crystalline forms and even an amorphous form.[14] This mixture of different crystalline forms of rifaximin (a C b, b, b C amorphous) and even the amorphous form have dif- ferent values of potency compared to the potency of rifaximin form a. The different combinations of rifaximin forms, a C b, b, b C amorphous, present melting point of approximately 217�C. The amorphous form presents greater solubility than the form a, b and the combinations a and b. However, it does not have the same excellent tolerability as the reference drug, form a.[17,18] Analytical methods Even with all its importance, all its uses and its superiority to other drugs, rifaximin lacks of the analytical methods in the lit- erature and in most official compendia for your quality control, because the drug’s efficiency is not enough if it does not present the quality required for its safe and effective use. Reliable and effective analytical methods are extremely important for the promotion of true and inducible results of the analyzed products. However, for this, the validation of ana- lytical methods is necessary as it ensures the capability of the method.[19,20] Rifaximin is not present in the investigated pharmaco- poeias.[21–23,72] The British Pharmacopoeia[24] and European Pharmacopoeia[25] only contemplate the monograph for rifaxi- min in raw material by high performance liquid chromatogra- phy (HPLC). The pharmaceutical product of rifaximin tablets is not yet present in any official compendium, which makes the specifica- tion of the final product indefinite. This can cause damage to the quality of medicines containing rifaximin released on the mar- ket, since the chemical-pharmaceutical industries do not have a quality control parameter established in official documents. The literature shows methods for detection of rifaximin in biological fluid as rat urine, mouse serum, human plasma and dried blood spots and milk by HPLC or high performance liq- uid chromatography coupled to mass spectrometry (HPLC- MS).[10,26–32] The literature also shows the detection of rifaximin in phar- maceutical product as tablets by spectrophotometry in the ultraviolet (UV),[33–36] visible (Vis)[37] and infrared region (IR),[38] capillary electrophoresis (CE),[39] thin layer chroma- tography (TLC)[40] high-performance thin-layer chro- matographic (HPTLC)[41]; HPLC[42–50] and HPLC-MS.[40] The literature also reports microbiological method for the calculation of the power of rifaximin by turbidimetry,[44] which is a more dynamic method than the traditional method by dif- fusion in agar. In the case of antimicrobials, the simultaneous evaluation of the material by physico-chemical and microbio- logical methods are extremely important. Physico-chemical methods do not always faithfully assess the potency of drugs such as antimicrobials made by the microbiological method. Care in working with these two types of techniques is funda- mental to ensure quality medicines for the population.[51–53] Dissolution method for tablets is important for the verifica- tion of dissolution profile and pharmacotechnical formula, since an excellent medicine is not sufficient if it does not dis- solve properly. Rifaximin presents a dissolution method with reading in spectrophotometer in the ultraviolet region.[54] The study of the stability of raw material and pharmaceuti- cal products is required throughout the world. The conditions used in this type of study, which includes short- and long-term stability studies, are recommended by International Conference on Harmonisation,[55] by National Agency of Sanitary Surveil- lance[56] and by guide of World Health Organization.[57] The monitoring of drug stability helps reveal the behavior and pos- sible product problems within the validity period. The literature shows the behavior of tablets of rifaximin during 6 months sub- jected to simultaneous conditions of temperature (40 § 2�C) and humidity (75 § 5%).[58] All these studies are essential, especially because rifaximin can present polymorphs with characteristics and therapeutic totally different and unwanted. Analytical differences can indi- cate the presence of different polymorphs. Universities have performed a fundamental role serving as research centers for the development and validation of analyti- cal methodologies, contributing to sanitary control activities and scientific enrichment in the area.[59] Table 1 shows the conditions of the methods for evaluation of rifaximin in biological fluids and pharmaceutical product, and Figure 2 illustrates their distribution. The use of methods, considered green, makes unnecessary the remediation of environmental impacts often observed today[6,60–63,70,7,64–66]. Some methods for evaluation of rifaxi- min contemplate this thought because they use only ethanol and water, instead of methanol in the UV method, for example, or simply just potassium bromide, as shown in Table 1. The thinking of green chemistry begins with the choice of analytical method to be used followed by apparatus and diluents. In this choice, suitability for the intended purpose must be sufficient and it cannot be based on the method that everyone uses or because it is fashionable. In a routine analysis, for example, is HPLC-MS really necessary? Is not UV or even TLC enough? Is the pre-column chromatographic necessary? CRITICAL REVIEWS IN ANALYTICAL CHEMISTRY 461 Ta bl e 1. M et ho ds fo re va lu at io n of rif ax im in in bi ol og ic al fl ui ds an d ph ar m ac eu tic al s. M et ho d Co nd iti on LO D ,L O Q an d/ or ra ng e Re co ve ry (% ) D et ec tio n M at rix Ti m e (m in ) Re fe re nc e LC C1 8 co lu m n (5 m m ,1 50 m m £ 4. 6 m m ). Th e m ob ile ph as e w as a m ix tu re of m et ha no l-a ce to ni tr ile -0 .0 5 m ol L¡ 1 m on o po ta ss iu m ph os ph at e- 0. 5 m ol L¡ 1 ci tr ic ac id (5 0: 25 :2 0: 5) 50 –2 00 m g m L¡ 1 99 .9 25 4 nm Re la te d su bs ta nc es — [5 0] LC -M S/ M S Re st ek Pi nn ac le C1 8 co lu m n (5 0 £ 2. 1 m m ,5 m m )w ith a m ob ile ph as e co ns is te d of am m on iu m ac et at e so lu tio n (1 5 m M ,p H 4. 32 )a nd m et ha no l 0. 5– 10 ng m L¡ 1 98 .2 –1 09 Q ua nt ifi ca tio n w as pe rf or m ed in po si tiv e m od e us in g SR M H um an pl as m a 2. 3 [1 0] LC Su pe lc o LC -H is ep (1 50 £ 4. 6 m m ,5 m m )u si ng ac et on itr ile : w at er :a ce tic ac id (1 8: 82 :0 .1 v/ v/ v) as a m ob ile ph as e 0. 03 ,0 .1 0 m g m L¡ 1 an d 0. 10 –2 0 m g m L¡ 1 — 23 3 nm Ra ts er um an d ur in e 13 .5 [2 9] 2D -L C- M S/ M S W at er s C1 8 co lu m n (1 50 £ 4. 6 m m ,5 m m )u si ng 0. 1% aq ue ou s ac et ic ac id :a ce to ni tr ile as m ob ile ph as e in a gr ad ie nt el ut io n m od e 0. 5– 10 ng m L¡ 1 — Po si tiv e m od e of io n de te ct io n w as us ed Ra ts er um 11 .0 [3 0] LC Lu na Ph en om en ax ,C 18 (1 50 m m £ 4. 6 m m i.d ., pa rt ic le si ze 5m ) co lu m n, m et ha no ll :1 0 m M ph os ph at e bu ffe r( 70 :3 0 v/ v pH ad ju st ed to 3. 0 by us in g or th ro ph os ph or ic ac id )a s m ob ile ph as e an d fl ow ra te of 1. 2 m L m in ¡1 at am bi en tt em pe ra tu re 0. 04 2, 0. 12 7 m g m L¡ 1 an d 5– 30 m g m L¡ 1 10 0. 31 29 3 nm Bu lk an d ta bl et s 5. 1 [4 7] Vi s Ri fa xi m in w as di ss ol ve d in m et ha no la nd di st ill ed w at er . O xi da tiv e co up lin g re ac tio n w ith fe rr ic ch lo rid e an d 3- m et hy l 1, 2 be nz ot hi az ol in e hy dr az on e hy dr oc hl or id e (M BT H )r ea ge nt w er e us ed . 0. 46 9, 1. 42 2 m g m L¡ 1 an d 5– 25 m g m L¡ 1 10 0. 03 63 7 nm Ta bl et s — [3 6] U V Ri fa xi m in w as di ss ol ve d in m et ha no l. Al ka lin e bo ra te bu ffe r( pH - 12 )w as us ed fo rt he di lu tio ns an d re ad in gs 0. 55 88 ,1 .6 93 4 m g m L¡ 1 an d 5– 25 m g m L¡ 1 10 0. 10 29 6 nm Ta bl et s — [3 6] LC -M S Zo rb ax SB C1 8, 4. 6 £ 75 m m ,3 .5 m m co lu m n, 10 m M am m on iu m fo rm at e (p H 4. 0) an d ac et on itr ile (2 0: 80 v/ v) as m ob ile ph as e at a fl ow ra te of 0. 3 m L m in ¡1 20 –2 0, 00 0 pg m L¡ 1 95 .7 –1 04 .2 m /z 78 6. 4 to 75 4. 4 in SR M H um an pl as m a 3. 4 [2 6] LC En d- ca pp ed oc ta de cy ls ily ls ili ca ge l( 25 m m £ 4. 6 m m )c ol um n at 40 � C us in g 37 vo lu m es of so lu tio n of am m on iu m fo rm at e (p H 7. 2) an d 63 vo lu m es of a m ix tu re of eq ua lv ol um es of ac et on itr ile an d m et ha no la s m ob ile ph as e. Fl ow ra te at 1. 4 m L m in ¡1 — — 27 6 nm Ra w m at er ia l — [2 4, 25 ] LC Sy m m et ry C1 8 co lu m n, ac et on itr ile :a m m on iu m ac et at e 85 :1 5 (v / v) as m ob ile ph as e an d fl ow ra te of 1 m L m in ¡1 .T he di lu en t of th e sa m pl es w as m et ha no l 0. 2, 0. 5 pp m an d 5– 50 pp m 99 .7 7 23 6 nm Ta bl et s 4. 3 [4 3] LC -M S Ch ro m ol ith Fl as h RP 18 e, (2 5 £ 4. 6 m m )c ol um n us in g m ob ile ph as e co ns is tin g of 0. 05 % fo rm ic ac id :a ce to ni tr ile (5 5: 45 v/ v) 0. 1– 10 ng m L¡ 1 98 .4 2 Po si tiv e m od e of io n w as us ed D rie d bl oo d sp ot s 2. 3 [3 1] LC C1 8 (1 50 m m an d 4 m m pa rt ic le si ze )c ol um n, m et ha no la nd am m on iu m ac et at e as m ob ile ph as e 30 ,1 50 ng m L¡ 1 an d 12 8– 51 3 ng 50 m L¡ 1 54 .1 7 45 5 nm M ilk 0. 5– 0. 6 [2 7] LC W at er s XT er ra RP 18 co lu m n (2 50 £ 4. 6 m m ,5 m m )w ith 0. 1% aq ue ou s ac et ic ac id :a ce to ni tr ile (4 5: 55 v/ v) as m ob ile ph as e 0. 01 ,0 .0 3 m g m L¡ 1 an d 0. 03 -1 0. 0 m g m L¡ 1 99 .5 23 9 nm Ra ts er um 6. 2 [3 2] LC C1 8 co lu m n us in g an aq ue ou s te tr a bu ty la m m on iu m hy dr og en su lp ha te :m et ha no l( 10 :9 0, v/ v) ,w ith fl ow ra te 1. 0 m L m in ¡1 0. 78 6, 0. 23 8 m g m L¡ 1 an d 1– 20 0 m g m L¡ 1 98 .7 0– 99 .7 1 45 4 nm Ta bl et s 3. 6 [4 5] H PT LC Al um in iu m pl at es pr ec oa te d w ith si lic a ge l6 0 F2 54 an d n- he xa ne :2 -p ro pa no l: ac et on e :a m m on ia (5 :4 .1 :1 ,v /v /v /v )a s m ob ile ph as e 61 .2 5, 18 5. 59 ng ba nd ¡1 an d 40 0– 32 00 ng ba nd ¡1 10 0. 35 –1 03 .1 2 Rf of 0. 59 § 0. 03 at 44 3 nm Bu lk an d ta bl et s — [4 1] LC Ch ro m os il Sy m m et ry C1 8 (1 50 £ 4. 6 m m ., 5 m m )c ol um n, ph os ph at e bu ffe rp H 4. 0 an d ac et on itr ile (4 0: 60 v/ v) as m ob ile ph as e an d fl ow ra te 1. 0 m L m in ¡1 0. 02 ,0 .1 0 m g m L¡ 1 an d 10 –6 0 m g m L¡ 1 10 0. 6– 10 1. 4 29 2 nm Bu lk an d ta bl et s 3. 0 [4 6] LC C1 8 co lu m n us in g an aq ue ou s te tr a bu ty la m m on iu m hy dr og en su lp ha te (1 0 m M )( pH 3. 37 ): ac et on itr ile (4 0: 60 ,v /v )a s m ob ile ph as e, fl ow ra te 1. 2 m L m in ¡1 0. 07 9, 0. 02 4 m g m L¡ 1 an d 0. 1- 20 0 m g m L¡ 1 98 .4 9– 98 .8 3 44 1 nm Bu lk an d ta bl et s 5. 7 [4 2] LC Sy m m et ry C1 8 co lu m n (1 50 £ 4. 6 m m ,5 m m ), fl ow ra te of 1 m L m in ¡1 an d m et ha no l: ph os ph at e bu ffe rp H 3 (p H w as ad ju st ed w ith or th op ho sp ho ric ac id ), 65 :3 5 v/ v, as m ob ile ph as e 20 -1 00 m g m L¡ 1 10 0. 30 45 4 nm Bu lk an d ta bl et s 2. 3 [4 9] 462 A. C. KOGAWA AND H. R. N. SALGADO U V Ri fa xi m in w as di ss ol ve d in et ha no la nd di st ill ed w at er 1. 39 ,4 .2 2 m g m L¡ 1 an d 10 –3 0 m g m L¡ 1 10 0. 17 29 0 nm Ta bl et s — [3 3] U V Th e so lu tio ns w er e m ad e in 0. 01 M N aO H 0. 30 1, 0. 91 2 m g m L¡ 1 an d 10 –5 0 m g m L¡ 1 99 .5 2 Fi rs td er iv at iv e at 29 2. 80 nm Sy nt he tic m ix tu re — [3 4] U V Th e so lu tio ns w er e m ad e in 0. 01 M N aO H 0. 21 4, 0. 64 8 m g m L¡ 1 an d 10 –5 0 m g m L¡ 1 > 99 .0 29 2 nm Sy nt he tic m ix tu re — [3 5] Tu rb id im et ric Ri fa xi m in w as di ss ol ve d in et ha no la nd di st ill ed w at er .T he co nc en tr at io ns us ed w er e 50 ,7 0 an d 98 m g m L¡ 1 50 -9 8 m g m L¡ 1 10 0. 70 53 0 nm Ta bl et s 4 ho ur s [4 4] LC Ec lip se Pl us TM C1 8 5 um as co lu m n, m ix tu re of w at er C 0. 1% gl ac ia la ce tic ac id an d et hy la lc oh ol in th e ra tio 52 :4 8 (v /v )a s m ob ile ph as e, fl ow ra te 0. 9 m L m in ¡1 an d in je ct io n vo lu m e at 20 m L — — 29 0 nm Ta bl et s — [4 4] LC -M S G em in iC 18 co lu m n (5 0 £ 2. 0 m m ,5 um ), ac et on itr ile :1 0 m M am m on iu m fo rm at e (in 0. 1% fo rm ic ac id )( 80 :2 0, v/ v) as m ob ile ph as e at a fl ow ra te of 0. 20 m L m in ¡1 an d po si tiv e io ni za tio n m od e 10 pg m L¡ 1 an d 10 –5 00 0 pg m L¡ 1 > 90 .6 4 SR M m od e an d m /z 78 6. 4 to 75 4. 3 H um an pl as m a 0. 9 [2 8] LC In er ts il C1 8 (2 50 £ 4. 6 m m ,5 m m )c ol um n, so di um ac et at e bu ffe r: ac et on itr ile (6 0: 40 v/ v pH ad ju st ed to 5. 0 by us in g N aO H )a s m ob ile ph as e w ith fl ow ra te 1. 0 m L m in ¡1 at 25 � C 0. 71 ,2 .1 60 m g m L¡ 1 an d 20 –8 0 m g m L¡ 1 — 29 3 nm Bu lk an d ta bl et s 3. 5 [4 8] Vi s Ri fa xi m in w as di ss ol ve d in et ha no la nd di st ill ed w at er 0. 30 75 ,0 .9 31 7 m g m L¡ 1 an d 15 –5 0 m g m L¡ 1 99 .1 2 47 7 nm Ta bl et s — [3 7] IR Ri fa xi m in w as di lu te d in po ta ss iu m br om id e (K Br ), pr ev io us ly dr ie d 0. 20 ,0 .6 1 m g an d 1. 0- 3. 5 m g 10 0. 13 17 67 –1 70 1 cm ¡1 Ta bl et s 10 [3 8] CE Ri fa xi m in w as di ss ol ve d in et ha no la nd di st ill ed w at er .T he se pa ra tio n w as pe rf or m ed us in g a si lic a ca pi lla ry ,b or at e bu ffe r2 5 m M pH 9. 5 an d 20 kV 10 .7 2, 32 .4 8 m g m L¡ 1 an d 50 –5 00 m g m L¡ 1 10 0. 24 29 0 nm Ta bl et s 2. 0 [1 8] TL C Si lic a ge la s st at io na ry ph as e an d et hy la ce ta te :e th yl al co ho l, 90 :1 0 (v /v ), as m ob ile ph as e — — Rf of 0. 62 at 25 4 nm Ta bl et s — [5 4] LC -M S Co lu m n Ec lip se Pl us TM C1 8 5 m m ,m ix tu re of w at er C 0. 1% gl ac ia la ce tic ac id an d et hy la lc oh ol in th e ra tio 52 :4 8 (v /v )a s m ob ile ph as e, fl ow ra te 0. 9 m L m in ¡1 an d in je ct io n vo lu m e at 20 m L. Io n tr ap m as s sp ec tr om et er ,A m aZ on SL Br uk er TM — — m /z 78 4 in th e ne ga tiv e m od e Ta bl et s 5. 5 [5 4] D is so lu tio n Pa dd le ap pa ra tu s at 50 rp m an d 90 0 m L of ac et at e bu ffe ro fp H 5. 0 C 0. 2% SL S as di ss ol ut io n m ed iu m — > 98 .9 2 29 0 nm Ta bl et s 60 [5 4] St ab ili ty Co nd iti on s of 40 § 2� C an d 75 § 5% re la tiv e hu m id ity — — — Ta bl et s 6 m on th s [5 8] LC D liq ui d ch ro m at og ra ph y; LC -M S D liq ui d ch ro m at og ra ph y co up le d to m as s sp ec tr om et ry ;2 D -L C- M S/ M S D tw o- di m en si on al re ve rs ed -p ha se liq ui d ch ro m at og ra ph y co up le d to m as s sp ec tr om et ry ;T LC D th in -la ye rc hr o- m at og ra ph ic ;H PT LC D hi gh -p er fo rm an ce th in -la ye rc hr om at og ra ph ic ;R fD re te nt io n fa ct or ;V is D sp ec tr op ho to m et ry in th e vi si bl e re gi on ;U V D sp ec tr op ho to m et ry in th e ul tr av io le tr eg io n; IR D sp ec tr op ho to m et ry in th e in fr ar ed re gi on ;C E D ca pi lla ry el ec tr op ho re si s; TL C D th in la ye rc hr om at og ra ph y; SR M D se le ct ed re ac tio n m on ito rin g. CRITICAL REVIEWS IN ANALYTICAL CHEMISTRY 463 Buffer solutions have a short half-life and always require new preparations, which make the process more expensive. Acetoni- trile, methanol and buffer solution are the diluents of choice for numerous analytical methods, but are they really needed? In the case of rifaximin, the answer is “no.” Ethanol and purified water were enough. Faster, low cost and without toxic solvents methods must be preferred for the quantification of rifaximin, focusing on the multi-dimensional impact of analytical decisions. The correct analytical choices can provide cheaper medicines on the market and more accessible to the population. This conscious and mature attitude relieves the public health system. The use of toxic solvents such as acetonitrile and metha- nol,[67] in addition to damaging the health and quality of life of the operator who is in direct and daily contact with the prod- uct, it also requires adequate waste treatment to avoid compromising the water, aquatic life, soil, plantations and animals.[68,69] Analysts are now called upon to think about the analytical decision itself, targeting all that it impacts[71]. They must also take into consideration the development and choice of cleaner, greener, faster and lower cost methods with less steps and consumables. Green analytical chemistry expects analysts who think beyond of the result of an analysis at any cost. Conclusion Rifaximin, a crystalline form, is an oral antimicrobial with minimal adverse effects. It is used since hepatic encephalop- athy until acute diarrhea. Its wide use reaches from children to debilitated people and the evaluation of the quality of products containing rifaximina is fundamental. Thus, ana- lytical methods are needed and currently they are seen by the look of green chemistry. Rifaximin presents in the liter- ature options of clean, green, efficient, cheap and fast ana- lytical methods by HPLC, UV, Vis, IR, CE and TLC. However, it still lacks a monograph in official compendium for evaluation of the final product. Conflicts of interest The authors declare no conflicts of interest. Acknowledgments The authors acknowledge CNPq (Bras�ılia, Brazil), FAPESP (S~ao Paulo, Brasil), CAPES (S~ao Paulo, Brasil) and PADC/FCF/UNESP (Araraquara, Brazil). ORCID Ana Carolina Kogawa http://orcid.org/0000-0003-2834-6532 H�erida Regina Nunes Salgado http://orcid.org/0000-0002-0385-340X References [1] Mullen, K. D.; Sanyal, A. J.; Bass, N. M.; Poordad, F. F.; Sheikh, M. Y.; Frederick, T.; Bortey, E.; Forbes, W. P. Rifaximin is Safe and Well Tolerated for Long-Term Maintenance of Remission from Overt Hepatic Encephalopathy. Clin. Gastroenterol. Hepatol. 2014, 12, 1390–1397. 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SALGADO https://doi.org/10.21474/IJAR01/1473 https://doi.org/10.9735/0975-5276.4.8.316-321 https://doi.org/10.9735/0975-5276.4.8.316-321 https://doi.org/10.1039/c3ay40847g https://doi.org/10.3390/pharmaceutics7030106 https://doi.org/10.17628/ecb.2017.6.359-364 https://doi.org/10.1021/ar010065m https://doi.org/10.1021/cr078380v https://doi.org/10.1021/cr068359e https://doi.org/10.1039/b103187m https://doi.org/10.1080/10408347.2016.1219649 https://doi.org/10.1080/10408347.2017.1281097 https://doi.org/10.1016/j.trac.2009.06.001 https://doi.org/10.1039/C5GC00340G http://www.inchem.org/documents/ehc/ehc/ehc154.htm http://www.inchem.org/documents/ehc/ehc/ehc154.htm http://www.inchem.org/documents/ehc/ehc/ehc196.htm https://doi.org/10.1351/pac200678111993 https://doi.org/10.1080/10408347.2017.1374165 Abstract Introduction Rifaximin Hepatic encephalopathy Treatment Irritable bowel syndrome Clostridium difficile Traveler's diarrhea Treatment Acute diarrhea Treatment Polymorphism Analytical methods Conclusion Conflicts of interest Acknowledgments References