Pharmaceutical quality of antimalarial drugs: quinine ...

RESEARCH Open Access

Pharmaceutical quality of antimalarialdrugs quinine sulfate and ArtemetherLumefantrine tablets sold on BukavuMarketAladin Ombeni Mahano1 Aline Zawadi Mahano1 Nelson Hendwa Cubaka1 Feacutelicien Mushagalusa Kasali1Benjamin Bavurhe Zirirane1 Lucien Murhula Namegabe1 Pacifique Murhula Hamuli1 andNtokamunda Justin Kadima12

Abstract

Background Generic antimalarial drugs sold in sub-Saharan Africa require tighter control as counterfeiting hasgrown more and more out of control The study aimed to analyze the pharmaceutical quality of quinine sulfate(QS) and ArtemetherLumefantrine(AL) tablets marketed in Bukavu city compared to the current trends in otherAfrican cities

Results The samples were purchased in community pharmacies or from ambulatory street vendors and analyzedusing a set of thirteen simple tests including visual inspection UV spectrometry TLC and conventional qualitycontrol procedures More than 93 of AL samples had an acceptable global quality score of gt 90 Around 166of QS batches did not satisfy the requirements about hardness friability and mass uniformity Only 333 met thedisintegration quality 333 did not contain quinine 833 had an active ingredient other than quinine

Conclusion The findings strongly alert the circulation of fake antimalarial medicines observed in many countriesSimple TLC procedures may help to detect any low-quality generics to avoid microbial resistance and guaranteethe health of the population Pharmacists and regulatory authorities are alerted to the circulation of low-qualitygeneric quinine preparations in the country

Keywords Quinine Artemether Lumefantrine Quality control Congo

BackgroundAround 32 billion people or almost half of the worldrsquospopulation are exposed to malaria risk [1ndash4] Accordingto the World Malaria Report (WMR) an estimated 228million malaria cases occurred worldwide in 2018 and19 countries in sub-Saharan Africa and India carried al-most 85 of the global malaria burden [1] Of an esti-mated 405000 deaths from malaria globally nearly 85

live in 20 countries in the WHO African Region mainlyNigeria (24) and the Democratic Republic of Congo(DRC) (11) [5 6] Children aged under 5 years are themost vulnerable group affected by malaria theyaccounted for 67 (272000) of all malaria deaths world-wide in 2018Access to adequate and quality antimalarial drugs

(AMDs) plays a crucial role in efforts to ensure completecures and avoid vicious complications [7] Without treat-ment malaria can quickly lead to death from the circula-tory disorders it causes Also in many parts of theworld malaria parasites have become resistant to several

copy The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 40 International Licensewhich permits use sharing adaptation distribution and reproduction in any medium or format as long as you giveappropriate credit to the original author(s) and the source provide a link to the Creative Commons licence and indicate ifchanges were made The images or other third party material in this article are included in the articles Creative Commonslicence unless indicated otherwise in a credit line to the material If material is not included in the articles Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use you will need to obtainpermission directly from the copyright holder To view a copy of this licence visit httpcreativecommonsorglicensesby40

Correspondence kadima48yahoocom ntokamunda13gmailcom1Department of Pharmacy Faculty of Pharmaceutical Sciences and PublicHealth Official University of Bukavu Bukavu Democratic Republic of Congo2Department of Pharmacy School of Medicine and Health SciencesUniversity of Rwanda Kigali Rwanda

Future Journal ofPharmaceutical Sciences

Mahano et al Future Journal of Pharmaceutical Sciences (2021) 7131 httpsdoiorg101186s43094-021-00290-8

AMDs due in significant part to fake medications [8ndash10] Among those counterfeit medicines some containsub-therapeutic doses and others not at all [11] Accord-ing to the molecular quantitative similarity analysis(MQSA) study 25ndash50 of AMDs are of low qualityadulterated or inferior quality The figures from the USFood and Drug Administration (USFDA) indicate thatup to 25 of all drugs consumed in emerging countriesare counterfeit or substandard [12ndash14] Counterfeitingaffects all classes of drugs but mainly antibiotics andAMDs for which the demand is high in African coun-tries where malaria is endemic That demand leads to aninformal trade in counterfeit products beyond the con-trol of health authoritiesIn the DRC an estimated 97 of the population lives

in zones with stable malaria transmission lasting 8 to 12months per year the other 3 is exposed to epidemicmalaria in the high mountains of the east of the country[15 16] Around 80 of deaths occur at home whichrepresents millions of cases of death per year The preva-lence of fever in children under 5 years of age is 42corresponding to between 6 and 10 malaria episodes perchild per year The combination ArtemetherLumefan-trine (CoArtem) and ArtesunateAmodiaquine (AS-AQ)are the most widely used AMDs in the initial treatmentof non-severe Falciparum malaria and quinine for severecases [17] The circulation of counterfeit or poor-qualityproducts is beyond control This study aimed to assessthe quality of generic quinine sulfate (QS) andArtemether-Lumefantrine (AL) tablets marketed in Bu-kavu using simple usual analytical techniques

MethodsStudy designThe study took place in Bukavu city the capital ofSouth-Kivu province in DRC from May to September2019 It assessed pharmaceutical technology require-ments concerning labeling physical examination disin-tegration time friability and mass uniformity Thin-layer chromatography (TLC) non-aqueous protometryand UV-spectrophotometry served to identify and assayactive ingredients using referral pharmacopeial guide-lines and regulations Critical attributes were labelingquality general tests on pharmaceutical dosage formscontent and dissolution identification and the presenceof unidentifiable impurities in formulations

Equipment chemicals and reagentsThe equipment included UV spectrophotometer (Phar-macia LKB Ultrrospec Plus Germany) chromatographicplates (pre-coated TLC sheets Alugramreg Xtra Sil GUV254 layer 020 mm silica gel 60 with fluorescent indica-tor UV 254) UV lamp 254 nm (Technology TransferGermany) analytical balance (balance digital jewelry

scale capacity 20 g readability 0001 g China) friabilitydevice (manufactured by lab-line instruments IncModel ndeg1641 China) aggregation device (Erweka-appa-rate bau Germany) durometer (Schleuniger-2ESwitzerland) hot plate (Protherm Winn Leek Holland)water bath (Gerhardt Bonn Germany) rotavapor (Pleu-ger Switzerland) centrifuge (IEC Centra-2 centrifugeUSA) and vortex shaker (Vortex-2 genie BohemiaUSA)The solvents were distilled water toluene R (Merck

KGaA 64271 Darmstadt Germany) ethyl acetate R(Merck KGaA 64271 Darmstadt Germany) methanol R(Maprochim-Labo 59 lot 0112 90 0791 DRC)hydrochloric acid R (PANREAC Quimica SAU E-08211Spain) glacial acetic acid R (BN 04H240011 Spain)acetic anhydride R (E Merck Darmstadt Germany)acetone R (Merck KGaA 64271 Darmstadt Germany)perchloric acid R (70 density 176 E Merck D-6100Darmstadt Germany) chloroform R (Prolabo Belgium)potassium iodide R (Merck D-6100 DarmstadtGermany) and mercury chloride II R (B ZedelgemGermany)

Method developmentUniformity of massIt represents the average mass of 20 tablets The devi-ation of the individual tablet weight from the meanweight should not exceed a minimum of plusmn 50 and amaximum of plusmn 100 for 18 and 20 tablets respectively[18]

Friability of tabletsA device manufactured by Lab-Line Instruments IncModel ndeg1641 operating by rotation at 100 revolutionsper 4 min served to measure friability with a total oftablets corresponding as near as possible to 65 g intro-duced in the machine According to the requirementthe maximum acceptable loss of mass (obtained from asingle test or the mean of 3 tests) is not greater than10 for the sample [19]

Hardness-resistance of tablets to crushingA durometer (Schleuniger-2E Switzerland) served tomeasure the minimum and maximum force (newton) tocrush each of 10 tablets [20]

Disintegration of tabletsWe used a 6-tube basket disintegrating device Erweka-apparate containing HCl 1 N as immersion fluid main-tained at 37 plusmn 2 degC in triplicate The basket filled withsix tablets was rotated for 30 min and then raised tocount the units not completely disintegrated At least 16of the 18 dosage units tested should disintegrate in time[21 22]

Mahano et al Future Journal of Pharmaceutical Sciences (2021) 7131 Page 2 of 8

Identification of quinine sulfate by Mayer reagentA tiny amount of crushed tablets powder was mixedwith distilled water filtered and the filtrate mixed withthe Mayer reagent (5 g of potassium iodide (KI) 136 gof mercury chloride (HgCl2) and 100 ml of distilledwater) in a test tube The reaction was positive if ayellowish-white precipitate is formed [23]

Identification of quinine sulfate and Artemether-Lumefantrine by TLCThe protocol followed the existing procedures withslight adaptation For QS samples [24ndash26] the stationaryphase was silica gel R6 the mobile phase was methanolammonia (20 05 vv) The final concentration was1428 mgml For AL samples [27 28] the stationaryphase was silica gel R6 the mobile phase was tolueneethyl acetateanhydrous acetic acid (1842 vvv) Thefinal concentration was 130 mgml of Artemether and780 mgml of Lumefantrine Approximately 2 μl of sam-ples and 2 μl of standards were spotted at 15 cm on sil-ica gel R6 plates After migration each chromatographicplate was removed dried and then examined with ultra-violet light (254 nm) for QS samples The identificationof AL samples required spraying the plate with sulfuricacid Rmethanol R mixture (10190 vv) and then heatingthe chromatographic plate to dryness on the heatingplate at 50 degC for approximately 10 min We comparedthe correspondence in position appearance and inten-sity between the test samples and the standards The re-tardation factor error (Rf error) of Rf-sample and Rf-standard was calculated as follows

RFerror frac14 100 RfstandardminusRfsampleeth THORNRfstandard

Rule If Rf error le 5 the sample is considered valid ifRferror is between 5 and 10 the analyte is deemeddoubtful if Rf error ge 10 it is invalid [2]

Quantitative analysis of quinine sulfate in tabletsAliquots of 20 tablets crushed to a powder equivalent to100 mg of quinine sulfate were gently stirred for 15 minin 40ml of acetic anhydride R and 40ml of anhydrousacetic acid And we titrated with perchloric acid (01molL) using violet crystal as the indicator (from violetto blue and apple green) Each milliliter of perchloricacid (01 moll) is equivalent to 2610 mg of quinine sul-fate [(C20H24N2O2)2 H2SO42H2O] The test requiresthat the yield be not less than 900 and not more than1100 of the amount of quinine sulfate [29 30]

Quantitative analysis of Artemether-LumefantrineThe principle consists of extracting Artemether andLumefantrine from TLC spots and measuring the

absorbance at 254 nm For the Artemether (sample andstandard) the layer obtained by TLC was carefullyscraped weighed and diluted with 2 ml of the HCletha-nol mixture (1 moll) in a test tube Afterhomogenization on the vortex the test tube was heatedin a water bath at 55 degC for 5 h then cooled to roomtemperature and centrifuged The procedure was thesame for the blank without Artemether The resultingsolutionrsquos absorbance was measured in a 1-cm layerquartz cell at 254 nm against a solvent cell containingthe blank The dilution was 385 for Artemether(C16H26O5) in the sample and standard using the ab-

sorptivity value A11cm frac14 385 [27] The percentage content

of Artemether (C16H26O5) in the tablets was calculatedas follows

Yield frac14 100 mean Asorbance sampleeth THORNmean Absorbance standard

The test met the requirement if the yield is between950 and 1050 of the amount of Artemether(C16H26O5) and Lumefantrine (C30H32Cl3NO) For thelumefantrine analysis the TLC layer spots were carefullyscraped weighed and dissolved in 2 ml of methanol R ina test tube The mixture was then homogenized on thevortex for 15 min and centrifuged The absorbance wasmeasured at 380 nm [28] against the blank prepared inthe same way without Lumefantrine

Data analysisWe set the score of the critical quality attributes as 1 or0 when the test met or not the requirementmdashthe sum ofscores allowed calculating the percentages of globalquality satisfaction The quality was excellent (090ndash100) good (080ndash090) acceptable (070ndash080) and low(030ndash070) based on a modified psycho-physical Har-ringtonrsquos scale of quality [31]The risk of treatment failure death due to untreated

disease or toxicity was high moderate or low concern-ing the absence or wrong active ingredient identityunder-dose over-dose disintegration uniformity ofmass and labeling outcomes MS Excel 2013 was usedto calculate the descriptive statistics

ResultsLabeling of medicinesThe samples of generic QS and AL tablets analyzed werefrom the community pharmacies and ambulatory streetvendors As shown in Table 1 QS samples consisted of12 batches containing 30 tablets each from 5 brands ALsamples consisted of 12 packs containing 24 tablets perblister from two brands As presented the visual inspec-tion shows that 4 (30) batches of QS samples (QSB22QSB24 QSB35 and QSB46) did not meet all the

labeling requirements Some information was inaccurateor missing The labeling on the packages of AL samplescontained all the needed information

Manufacturing technology qualityThe elements tested were mass uniformity hardness fri-ability and disintegration time For QS samples twobatches (QSB46 QSB57) did not meet the mass uni-formity criteria because more than three tablets deviatedbeyond plusmn 100 The hardness of 2 batches (QSB13QSB34) did not lay between 50 and 150 N The disinte-gration time of 8 batches (QSB11 QSB13 QSB18QSB19 QSB111 QSB22 QSB24 and QSB35) was outof specification limits For AL samples two batches(ALB14 ALB22) did not meet the mass uniformity cri-teria All batches satisfied the specification limits ofhardness friability and disintegration

Identification of active ingredientsFigure 1 shows the typical TLC chromatogramsobtainedIdentification of QS samples showed that four batches

(QSB57 QSB510 QSB512 QSB46) did not containquinine sulfate QSB46 had an active ingredient otherthan quinine sulfate because the Rferror was gt 10 Fourbatches of QS samples failed Mayerrsquos reaction (QSB46QSB57 QSB510 and QSB512)

Content assay of active ingredientsTable 2 shows the results of quantitative assays For QSsamples the batches QSB46 QSB47 QSB410 andQSB412 did not contain quinine (yield = 0) Thequalitative analysis revealed the absence or insufficientamount of active ingredients or the presence of othercomponents than quinine sulfate in some batches

Table 1 Samples of quinine sulfate and Artemether-Lumefantrine brands tested

Quinine sulfate tablets samples Artemether-Lumefantrine tablets samples

N Batch Dose mg Shelf life Country N Batch Dose mg Shelf life Country

1 QSB11 500 5 years Democratic Republic of Congo 1 ALB11 20120 3 years Uganda

6 QSB22 500 6 years Missing 6 ALB19 20120 3 years Uganda

8 QSB35 500 Missing Missing 8 ALB112 20120 3 years Uganda

9 QSB46 500 Missing Missing 9 ALB22 20120 3 years Turkey

10 QSB57 500 5 years Netherlands 10 ALB23 20120 3 years Turkey

Fig 1 Typical TLC chromatograms of Artemether (A)Lumefantrine (L) samples at the left and three quinine samples (A B C) at right The TLC ofLumefantrine (L) and Artemether (A) shows that all batches in triplicate spots gave Rf similar to the standards(s) with Rferror lt 2 for all the spotsHowever the TLC of quinine shows the absence of quinine sulfate in sample spot A(q2) the similarity of B(q1) and B(q2) spots with the standard(s) the presence of other products different from the quinine standard in C(q1) and C(q2)

For AL samples the yield of Lumefantrine batchesALB15 ALB17 ALB18 and ALB23 was lt 90

Global quality scoresFigure 2 shows the satisfaction of each QS batch to the14 tests performed using score 1 (if the requirement issatisfied) or 0 (if not) to evaluate the critical qualityattributesIt appears that no quinine batch obtained a 100

score the maximum score was 929 corresponding toone failure (QSB111 QSB18 QS11) and the minimumwas 357 corresponding to 9 fails (QS46) For ex-ample batches QSB22 QSB24 QSB35 and QSB46

(from brands 2 3 and 4) did not satisfy all required la-beling information all batches of brands 1 2 and 3failed the disintegration test all samples of brands 4 and5 did not contain quinine The most failed tests weredisintegration (333) and assay (417)Figure 3 shows the satisfaction of each AL batch to

the 13 tests performed also using score 1 (if the require-ment is satisfied) or 0 (if not) to evaluate the criticalquality attributes All labeling information needed wasgiven However only five batches satisfied the assay test(ALB11 ALB14 ALB112 ALB22 ALB210) The mini-mum score for AL batches was 923 The most failedtest was the assay (417)

DiscussionCounterfeiter medicines are the leading cause of resist-ance morbidity mortality and dysfunction failure of thepublic health care system interest [32ndash36] Quinine andArtemetherLumefantrine fixed-dose are on the WHOessential medicines model list for curative malaria [32]In this study we assessed the pharmaceutical quality ofQS and AL tablets under the following critical qualityrequirements labeling quality general tests on pharma-ceutical dosage forms content and dissolution identifi-cation and the presence of unidentifiable impurities informulations The findings vigorously back the import-ance of the counterfeiting phenomenon as described innumerous studiesDrug labeling is a legislative requirement to obtain in-

formation on drugs such as brand name pharmaceuticalform manufacture and expiration dates administrationroute manufacturer and country manufacturing [37]

Table 2 Results of quantitative assays

QS batches Quinine AL batches Artemether Lumefantrine

Batches Yield () Batches Yield () Yield ()

QSB11 9651 plusmn 199 AL B11 9946 plusmn 293 9815 plusmn 049

QSB18 10131 plusmn 151 ALB15 10019 plusmn 191 8037 plusmn 040

QSB46 0 ALB22 9678 plusmn 033 10037 plusmn 059

Out-of-specifications

Fig 2 Quality compliance scores of quinine batches analyzed Dose (the content strength) no batch (batch number) issue (the issued date)expire (the expiring date) shelf (the shelf life) company (the manufacturer) country (the country of production) uniformity (the uniformity ofmass) hardness (the resistance) friability (friction) disintegration (disintegration time) TLC (chromatogram) assay (dosage) and Mayer(identification of alkaloids)

Thus the investigated products might not have a risk ofconfusion associated with labeling The visual inspectionresults on the physical characteristics of tablets and la-beling information revealed that QS products did notcomply with the WHO guideline on the labeling forpharmaceutical products All QS samples mentioned thedose 833 mentioned batch number and date of issueand shelf life only 667 mentioned the manufacturerand country AL samples complied satisfactorily A tigh-ter inspection of the label can help suspect wrong prod-ucts Often counterfeiters copy the brandrsquos design or thedesignation of a product and sometimes the address Indeveloped countries anticounterfeit packaging technolo-gies are being developed [38ndash40] The European trend istowards 2D barcodes (anticounterfeit technologies) andthe USA has implemented radio frequency identification(RFID) [41] The probability of detecting the failure inDRC is lowAccording to Good Manufacturing Practice (GMP)

uniform mass and friability are also critical attributes ofquality [36 42 43] Failure to quickly release the activeingredient for conventional formulations has the risk oftherapeutic loss or delayed effect onset explaining thenumber of deaths The analysis of AL brands indicatedthat all of the samples but one complied with the qualityspecifications However for QS samples only 3 out of12 batches fully satisfied the critical technology attri-butes Also mass uniformity is an alternative test forcontent uniformity of uncoated and film-coated tabletsHere defaults of two QS batches and one AL batchmight not affect the content uniformity of the investi-gated productsrsquo dose units Many studies show that most

antimalarial solid dosage forms pass the basic tests suchas the uniformity of mass for tablets the content testbut a few pass in vitro product dissolution test required[36 42 43]TLC and Mayerrsquos QS identification revealed that 7 out

of 12 batches did not contain the active principle Theresults of quinine amount indicated that only 417 ofinvestigated products did comply with thepharmacopoeial specification limit (90ndash110) Contrar-ily AL samples showed excellent scores (gt 90) forArtemether even though the content of Lumefantrinewas under-dose in 4 batches The risk of treatment fail-ure due to bad quality is significantly higher with QStablets than AL fixed-dose products Studies carried outin Rwanda and the east of DR Congo had also shownthe under-dosing and the absence of the quinine [1144] One study conducted in DRC [45] on 150 AL sam-ples collected from private pharmaceutical outlets in 8main cities (Goma Kikwit Kinshasa Kisangani Lubum-bashi Matadi Mbandaka and Mbuji-Mayi) found 3 (2)visual inspection failure and 4 (27) TLC test failureHPLC assays showed 46 (307) samples had Arte-mether contents below 90 and 17 (113) above 110of the content claimed on the label 32 (217) sampleshad lumefantrine content below 90 and 8 (53) above110 Studies in Kenya [46] Burkina Faso [47] andEthiopia [48] also detected under-dose artemisinin gen-eric productsAccording to the WHO counterfeit AMDs are often

sold at low prices because they do not contain the rightingredients Oral administration is the most widely ac-cepted route due to its convenience in self-

Fig 3 Quality compliance scores of ArtemetherLumefantrine batches analyzed

administration and easy manufacturing which lead toeasy counterfeiting In DRC pharmacies and free mar-kets are among the potential sellers of inexpensive anti-malarial to health facilities and the public Theunemployment rate is high the average monthly house-hold income remains low [49] Such poverty leadspeople to look for cheaper antimalarial products sold infree markets The situation makes it very hard to detectfake products quickly Non-pharmacists own most phar-macies and many are not at all managed by pharmacistsOne knows that non-pharmacist health professionals arenot qualified to detect the quality characteristics of thedrugs they prescribe or administer

ConclusionThe findings show that antimalarial drugs sold in theDRC pharmaceutical market are imported products fromvarious countries and not all brands are of good qualityAfrican countries face multiple kinds of counterfeitingfavored by poverty lack of proxy control tools and inef-ficacy of regulatory authority That raises the importanceof surveying the quality of all pharmaceutical productsimported Pharmacists should be involved at each stepof the medication management system to detect anyanomalies to minimize the counterfeiting phenomenonimpact Simple tests may be of significant help

AbbreviationsAL Artemether-Lumefantrine ALB Artemether-Lumefantrine fixed-dosebatch AMD Antimalarial drug DRC Democratic Republic of the CongoGMP Good Manufacturing Practice MQSA Molecular quantitative similarityanalysis QS Quinine sulfate QSB Quinine sulfate batch RFID Radio-frequency identification TLC Thin-layer chromatography WHO Word HealthOrganization WMR World Malaria Report

AcknowledgementsThe authors are thankful to the laboratory technicians in the Department ofPharmacy (UOB)

Authorsrsquo contributionsAOM and AZM designed the study and literature search AZM LMN andPMH operated the pharmaceutics testing NHC FMK and BBZ conducted theidentification tests AOM and NJK revised the protocols and supervised andwrote the final draft All authors have read and approved the manuscript

FundingNot applicable

Availability of data and materialsAll data is available upon request

Declarations

Ethics approval and consent to participateNot applicable

Consent for publicationNot applicable

Competing interestsThe authors declare that they have no competing interests

Received 17 March 2021 Accepted 22 June 2021

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Jan 20202 CDC Malaria (2015) httpswwwcdcgovmalariaabout[fr-fr]-faqshtml

Accessed 20 Jan 20203 Trampuz A Jereb M Muzlovic I Prabhu RM (2003) Clinical review severe

malaria Crit Care 7(4)315ndash323 httpslinkspringercomcontentpdf101186cc2183pdf

4 Brooker SJ Clarke S Deepika Fernando CWG Nankabirwa J Schellenberg DGreenwood B (2017) Chapter 14 Malaria in middle childhood andadolescence In Child and Adolescent Health and Development 3rd ednWashington (DC) httpswwwncbinlmnihgovbooksNBK525246

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8 Basco L (2004) Molecular epidemiology of malaria in Cameroon-XIX Qualityof antimalarial drugs used for self-medication Am J Trop Med Hyg 70(3)245ndash250 httpsdoiorg104269ajtmh200470245

9 Winstanley P Ward S Snow R Breckenridge A (2004) Therapy of falciparummalaria in sub-Saharan Africa from molecule to policy Clin Microbiol Rev17(3)612ndash637 httpsdoiorg101128CMR173612-6372004

10 Takata J Sondo P Humphreys GS Burrow R Maguire B Hossain MS Das DCommons RJ Price RN Guerin PJ (2020) The WorldWide AntimalarialResistance Network Clinical Trials Publication Library a live open-accessdatabase of Plasmodium treatment efficacy trials Am J Trop Med Hyg103(1)359ndash368 httpsdoiorg104269ajtmh19-0706

11 Habyalimana V Mbinze JK Yemoa AL Kadima NJL Hubert P Roland MariniRD (2017) Simple LC isocratic methods development validation andapplication in the analysis of poor quality antimalarial medicines Am J AnalChem 8(9)582ndash603 httpsdoiorg104236ajac201789042

12 OMS (2012) Meacutedicaments essentiels frauduleux depuis lrsquoAsie du Sud et delrsquoEst vers lrsquoAfrique de lrsquoOuest httpswwwunodcorgdocumentstocReportsTOCTAWestAfricaWest_Africa_TOC_FRAUD_MEDICINES_FRpdf

13 Frankish H (2003) WHO steps up campaign on counterfeit drugs Lancet3621730 httpsdoiorg101016S0140-6736(03)14891-X

14 Kelesidis T Falagas ME (2015) Substandardcounterfeit antimicrobial drugsClin Microbiol Rev 28(2)443ndash464 httpsdoiorg101128CMR00072-14

15 Ministere de la santeacute publique (MSP) (2011) Rapport narratif Profilpharmaceutique de la Reacutepublique Deacutemocratique du Congo

16 National Malaria Control Program (2018) Evaluation of the impact of malariacontrol interventions on all-cause mortality in children under five in theDemocratic Republic of the Congo from 2005 to 2015 Kinshasa httpswwwpmigovdocsdefault-sourcedefault-document-librarypmi-reportsdrc-malaria-impact-evaluation-group-executive-summary-frenchpdfsfvrsn=3 Accessed 15 Aug 2019

17 WHO (2019) Artemisinin resistance and artemisinin-based combinationtherapy efficacy Global Malaria httpswwwwhointmalariaareastreatmentdrug_efficacyen Accessed 15 Aug 2020

18 WHO (2019) Uniformity of mass for single-dose preparations 9th edn TheInternational Pharmacopoeia (PhInt) httpsappswhointphintpdfb75352-Uniformity-of-mass-for-single-dose-preparationspdf Accessed 15 Aug2020

19 EDQM 297 (2008) Friability of uncoated tablets In EuropeanPharmacopoeia (Ph Eur)Ph Eur 6th edn European Directorate for theQuality of Medicines Strasburg p 278 httpwwwuspbpepcomep60297

20 EDQM 298 (2008) Resistance to crushing of tablets In EuropeanPharmacopoeia (Ph Eur) 6th edn European Directorate for the Quality ofMedicines Strasburg p 279 httpwwwuspbpepcomep60298

21 EDQM 291 (2008) Disintegration of tablets and capsules In EuropeanPharmacopoeia (Ph Eur) 6th edn European Directorate for the Quality ofMedicines Strasburg p 263 httpwwwuspbpepcomep60291

22 World Health Organization (2019) Disintegration test for tablets andcapsules 9th The International pharmacopoeia (PhInt) httpsappswhointphintpdfb75453-Disintegration-test-for-tablets-and-capsulespdf

23 World Health Organization (2019) Quinine sulfate tablets (Quinini sulfascompressi) 9th edn The International Pharmacopoeia httpsappswhointphint2019indexhtmldb622114

24 Richard J Peter P Peter G Schuster A (2016) Tests de chromatographie surCouche Mince Global Pharma Health Fung(GPHF) Allemagne p 209

25 Gaur R Azizi M Hansal P Harper K (2009) Stationery Office on behalf of theMedicines and Healthcare product Regulatory Agency (MHRA) BritishPharmacopoeia London ISBN 9780 113227990

26 Rwo J Dwornik K Fischer K (2014) Thin layer chromatographic tests In AConcise Quality Control Guide on Essential Drugs and other Medicines 2ndedn Global Pharma Health Fund (GPHF) Darmstadt httpswwwgphforgimagesdownloadsDemoMinilabSupplement2014Englishpdf

27 WHO (2016) Artemether tablets In The International Pharmacopoeia (PhInt)6th edn Geneva httpsappswhointphint2016indexhtmldb62217

28 Karajgi SR Tanveer AR Kalyane NV (2020) Simultaneous determination ofArtemether and Lumefantrine by area under curve UV spectrophotometricmethod J Pharm Sci Res 12(2)258ndash263

29 WHO (2018) Quinine sulfate tablets final text for addition to theInternational Pharmacopoeia httpswwwwhointmedicinespublicationspharmacopoeiaQuinine-sul-tab_QAS07_219FINALpdf

30 Cholvy S (1960) Practical applications of protometry in anhydrous media forthe analytical control of some pharmaceutical preparations Ann Pharm Fr18138ndash144 httpspubmedncbinlmnihgov13809987

31 Bikbulatov ES Stepanova IE (2011) Harringtonrsquos desirability function fornatural water quality assessment Russ J Gen Chem 81(13)2694ndash2704httpsdoiorg101134S1070363211130111

32 World Health Organization (2019) World Health Organization model list ofessential medicines 21st edn Geneva pp 1ndash60 httpsappswhointirisbitstreamhandle10665325771WHO-MVP-EMP-IAU-201906-engpdf

33 Newton PN Green MD Mildenhall DC Planccedilon A Nettey H Nyadong Let al (2011) Poor quality vital antimalarials in Africa - an urgent neglectedpublic health priority Malar J 122

34 Rana GS (2005) Counterfeit defeat brands SSRN Electron J httpspapersssrncomsol3DeliverycfmSSRN_ID701189_code464609pdfabstractid=701189ampmirid=1

35 WHO (2010) Counterfeit medical products Geneva httpappswhointgbebwhapdf_filesWHA63A63_23-enpdf Accessed 15 Aug 2019

36 World Health Organization (2009) Does quality of medicines matter Geneva httpwwwwhointmedicinesservicescounterfeitfaqsQACounterfeit-October2009pdf

37 Nayyar GML Breman JG Newton PN Herrington J (2012) Poor-qualityantimalarial drugs in Southeast Asia and sub-Saharan Africa Lancet InfectDis 12(6)488ndash496 httpsdoiorg101016S1473-3099(12)70064-6

38 Moore S (2012) Labelling and its role in pharmaceutical packaging IntPharm Ind 4(3)114ndash118 Available from httpipimediaworldcomwp-contentuploads201209Pages-from-IPI-Volume4Issue3-35pdf

39 Bansal D Malla S Gudala K Tiwari P (2013) Anti-counterfeit technologies apharmaceutical industry perspective Sci Pharm 81(1)1ndash13 httpsdoiorg103797scipharm1202-03

40 Shah RY Prajapati PN Agrawal YK (2010) Anticounterfeit packagingtechnologies J Adv Pharm Technol Res 1(4)368ndash373 httpsdoiorg1041030110-555876434

41 Centers for Disease Control and Prevention (CDC) Epi InfoTM PopulationSurvey or Descriptive Study 7th edn Division of Health Informatics ampSurveillance Atlanta Georgia httpswwwcdcgovepiinfouser-guidestatcalcsamplesizehtml

42 Yapar EA (2014) Orally disintegrating tablets an overview J Appl Pharm Sci4(2)118ndash125 httpwwwjapsonlinecom httpsdoiorg107324JAPS201440219

43 Sastry SV Nyshadham JR Fix JA (2000) Recent technological advances inoral drug delivery - a review Pharm Sci Technol Today 3(4)138ndash145 httpsdoiorg101016S1461-5347(00)00247-9

44 Namegabe LM Kadhesi MT Hamuli PM Mahano AO Brioen PB (2019)Quality control of quinine in pharmaceutical forms tablets found in east ofthe Democratic Republic of Congo Am J Anal Chem 10(9)415ndash422 httpsdoiorg104236ajac2019109029

45 Mufusama JP Ndjoko Loset K Feineis D Hoellein L Holzgrabe UBringmann G (2018) Quality of the antimalarial medicine Artemether ndashLumefantrine in 8 cities of the Democratic Republic of the Congo DrugTest Anal 10(10)1599ndash1606 httpsdoiorg101002dta2420

46 Atemnkeng MA De Cock K Plaizier-Vercammen J (2007) Quality control ofactive ingredients in artemisinin-derivative antimalarials within Kenya andDR Congo Tropical Med Int Health 12(1)68ndash74 httpsonlinelibrarywileycomdoiepdf101111j1365-3156200601769x

47 Tipke M Diallo S Coulibaly B Stoumlrzinger D Hoppe-Tichy T Sie A Muumlller O(2008) Substandard antimalarial drugs in Burkina Faso Malar J 7(1)95httpsdoiorg1011861475-2875-7-95

48 Belew S Suleman S Mohammed T Mekonnen Y Duguma M Teshome HBayisa B Wynendaele E DrsquoHondt M Duchateau L De Spiegeleer B (2019)Quality of fixed dose ArtemetherLumefantrine products in Jimma ZoneEthiopia Malar J 18(1)236 httpsdoiorg101186s12936-019-2872-1

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Abstract
- Background
- Results
- Conclusion
- - Background
  - Methods
  - - Study design
    - Equipment chemicals and reagents
    - Method development
    - - Uniformity of mass
      - Friability of tablets
      - Hardness-resistance of tablets to crushing
      - Disintegration of tablets
      - Identification of quinine sulfate by Mayer reagent
      - Identification of quinine sulfate and Artemether-Lumefantrine by TLC
      - Quantitative analysis of quinine sulfate in tablets
      - Quantitative analysis of Artemether-Lumefantrine
      - Data analysis
        
        Results
        
        Labeling of medicines
        
        Manufacturing technology quality
        
        Identification of active ingredients
        
        Content assay of active ingredients
        
        Global quality scores
        
        Discussion
        
        Conclusion
        
        Abbreviations
        
        Acknowledgements
        
        Authorsrsquo contributions
        
        Funding
        
        Availability of data and materials
        
        Declarations
        
        Ethics approval and consent to participate
        
        Consent for publication
        
        Competing interests
        
        References
        
        Publisherrsquos Note

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