Medicines informal market in Congo, Burundi and Angola: counterfeit and sub-standard antimalarials
© Gaudiano et al; licensee BioMed Central Ltd. 2007
Received: 10 October 2006
Accepted: 22 February 2007
Published: 22 February 2007
The presence of counterfeits and sub-standards in African medicines market is a dramatic problem that causes many deaths each year. The increase of the phenomenon of pharmaceutical counterfeiting is due to the rise of the illegal market and to the impossibility to purchase branded high cost medicines.
In this paper the results of a quality control on antimalarial tablet samples purchased in the informal market in Congo, Burundi and Angola are reported. The quality control consisted in the assay of active substance by means of validated liquid chromatographic methods, uniformity of mass determination, disintegration and dissolution tests. Moreover, a general evaluation on label and packaging characteristics was performed.
The results obtained on thirty antimalarial tablet samples containing chloroquine, quinine, mefloquine, sulphadoxine and pyrimethamine showed the presence of different kinds of problems: a general problem concerning the packaging (loose tablets, packaging without Producer name, Producer Country and sometimes without expiry date); low content of active substance (in one sample); different, non-declared, active substance (in one sample); sub-standard technological properties and very low dissolution profiles (in about 50% of samples). This last property could affect the bioavailability and bioequivalence in comparison with branded products and could be related to the use of different excipients in formulation or bad storage conditions.
This paper evidences that the most common quality problem in the analysed samples appears to be the low dissolution profile. Here it is remarked that the presence of the right active substance in the right quantity is not a sufficient condition for a good quality drug. Dissolution test is not less important in a quality control and often evidences in vitro possible differences in therapeutic efficacy among drugs with the same active content. Dissolution profile can be dramatically affected by the choice of excipients in the oral solid formulation and, in many cases, is out of specifications due to the absence of formulation studies by producers of developing countries.
One of the effects of poverty is that the medicines market in developing countries consists essentially of illegal vendors. The economic restrictions, the weak drug-regulatory systems and the insufficient controls on production, distribution and importation promote a rise of the illegal medicines market . Moreover, the necessity of lowering the treatment costs induces the diffusion in the market of loose medicines, without the original primary packaging, of which, in many cases, the producer name and country, the batch number and the expiry date are not available, thus preventing any possible control of the origin and the quality of the drug, as recommended by the World Health Organization (WHO) . Furthermore, storage and selling conditions are inadequate: in many developing countries, drugs are maintained at high temperature and humidity, not in the original packaging and not protected from the sun. These conditions accelerate the drug degradation process with, in some cases, a lowering of the active substance strength and an increase of degradation products and, possibly, of toxicity . Moreover, storage conditions in tropical regions could affect the drug release profile, as evidenced in medicines from the Tanzanian market . The low quality (sub-standard) medicines and the presence of counterfeits, together with a poor adherence to therapy by the patient, are important causes of death in developing countries [5, 6]. In clinical trials, the therapies are well-monitored and the medicines are of good guaranteed quality, but the real therapeutic conditions are very different. Most individuals buy cheap medicines in the informal/illegal market without taking into consideration the risk of it. On the other hand, in most of sub-Saharan countries, the patients have no choice, because the only chance to purchase medicines, when they exist, is through the informal market. This situation favours the development of the illegal traffic of counterfeits. The evaluation of counterfeit and sub-standard medicines in developing countries is about 25% of marketed medicines but, in some countries, this percentage may increase up to 60% . WHO defines a counterfeit medicine as one which is deliberately and fraudulently mislabelled with respect to identity and/or source. Counterfeiting can apply to both branded and generic products and counterfeit products may include products either with correct ingredients, with the wrong ingredients, without any active ingredients, with incorrect quantity of active ingredients or with fake packaging . In developing countries, most counterfeit are of life-saving medicines such as antibiotics, antimalarials, anti-tuberculosis and antiretroviral drugs [9–17]. Every year many cases of counterfeit essential drugs causing therapy inefficacy, development of drug resistance and sometimes death are reported [18–21]. Considering the WHO definition of a counterfeit medicine, how should one consider medicines in plastic bags or enveloped in pieces of paper without any producer name, batch number or expiry date, being sold by non-authorized vendors? What is the real quality of these medicines? What are the real strength, the impurities quantity, the pharmaceutical-technological properties and the bioavailability of these medicines?
In this paper the results of a quality control performed on antimalarial tablets purchased by random sampling in the illegal/informal market in the capitals of Congo, Burundi and Angola are reported. The assay of the active substances was performed by reversed phase liquid chromatography (RP-LC). The uniformity of mass determination, the tablet disintegration and dissolution tests were also carried out. The last was performed to obtain in vitro information on possible bioavailability problems .
Commercial tablet samples of quinine, sulphadoxine and pyrimethamine, chloroquine, mefloquine were purchased from illegal vendors or in small informal pharmacies in Goma (Congo), Bujumbura (Burundi) and Luanda (Angola). Different samplings were performed in different places of these cities with the aid of local health professionals. For each sample the site of purchase, the cost, the environmental conditions (e.g. open stall, without protection from sun, etc.), the product name, the strength, the producer name and country (if available), the batch number and the expiry date (if available), was recorded. The samples were then sent by air to the Istituto Superiore di Sanità in Italy, where analytical controls were performed on thirty antimalarial tablet samples. Italian commercial antimalarial tablet samples were used for comparison in dissolution tests and in the analytical method development and validation. Quinine 250 mg tablets (Nova Argentia, Milano, Italy), chloroquine 250 mg tablets (Bayer AG Leverkusen, Germany), mefloquine 250 mg tablets (Roche S.p.A. Milano, Italy) were purchased from the Italian national market. Sulphadoxine and pyrimethamine (500 mg/25 mg) tablets (Roche Pharma, Reinach, Suisse) were purchased from the Vatican State Pharmacy.
Chloroquine diphosphate salt (purity>98%), quinine sulphate salt USP (purity = 99.8%) and pyrimethamine (purity>99%) used in standard preparations were purchased from Sigma Chemical Company (St. Louis, MO, USA). Mefloquine hydrochloride and sulphadoxine reference standards were obtained from the European Pharmacopoeia (EDQM, Strasbourg, France). Potassium dihydrogen phosphate was from ICN Biomedicals Inc. (Ohio, USA), 85% phosphoric acid was from Friedel-de Haen GmbH (Germany); 1-pentane-sulfonic acid sodium salt and 99.5% triethylamine were from Sigma-Aldrich GmbH (Steinthem, Germany), HPLC-grade methanol and acetonitrile were from Baker (Deventer, Holland). All other reagents were of analytical grade.
The chromatographic equipment consisted of a Series 1100 HPLC system with an automatic injector and a photo-diode array detector (Agilent Technologies Deutschland GmbH, Waldbronn, Germany). For data collection and calculation Chemstation software was used (Agilent Technologies). For the analysis of quinine, chloroquine and mefloquine tablets, a single method, previously validated, was employed . Samples were prepared by suspending the suitable quantity of powder from tablets in phosphate buffer (for chloroquine) and in methanol (for quinine and mefloquine) to obtain, after centrifugation, a final concentration of 0.1 mg/ml in active substance. Quantification of medicinal samples was obtained in triplicate analysis by comparison with standard solutions prepared in triplicate. The chromatographic column was a Symmetry C18, 75 mm × 4.6 mm i.d., 3.5 μm particle size (Waters Corporation, Massachussetts, USA) thermostated at 30°C. The detection wavelength was 230 nm and the injection volume was 10 μl. Mobile phase A was a buffer consisting of 50 mM potassium dihydrogen phosphate, 7 mM 1-pentane-sulfonic acid sodium salt and 0.1% v/v triethylamine. The pH was adjusted to 2.9 ± 0.1 with phosphoric acid before bringing to volume. Mobile phase B was acetonitrile. The elution was a gradient delivered at 1 ml/min as follows: 0–5 min: from 90% A to 70% A, 5–8 min: from 70% A to 50% A, 8–10 min: 50% A. The system was then re-equilibrated to 90% A.
Validation data of the LC method for sulphadoxine and pyrimethamine tablets analysis.
Y = 26873 X - 3
Y = 19603 X + 2
MEANn = 6 (%RSD)
MEANn = 6 (%RSD)
MEANn = 6 (%RSD)
MEANn = 3 (%RSD)
Linear equation (measured % vs added %)
Y = 1.05 X + 97.9
Y = 1.01 X + 100.7
Other quality control tests
The Uniformity of Mass was determined on each sample according to the European Pharmacopoeia . Disintegration test was performed following the method and limits reported in the European Pharmacopoeia  by using a PTZ AUTO disintegration apparatus (Pharma Test Apparatebau GmbH, Hainburg, Germany). Six tablets of each sample were placed inside the disintegration apparatus filled with distilled water at 37°C and the disintegration was verified after 15 minutes. For sugar coated tablets disintegration was verified after 60 minutes as indicated in the European Pharmacopoeia. Dissolution Test was performed following the specific methods described in the United States Pharmacopoeia  by using an AT7 Smart dissolution apparatus (Sotax Italia, Milano, Italy) connected with a Lambda 26 spectrophotometer (PerkinElmer, Wellesley, USA). For quinine tablets a dissolution medium consisting of 0.1N hydrochloric acid was employed, for chloroquine the medium was distilled water and for sulphadoxine and pyrimethamine tablets phosphate buffer at pH = 6.8 was used. The dissolution profiles for chloroquine and quinine were obtained by measuring the absorbance at 343 nm and 248 nm, respectively. For sulphadoxine and pyrimethamine the dissolution profiles were obtained by LC assay.
Results and Discussion
Information about the vendor, the price and the storage conditions were obtained from the filled in form attached to each sample. In more than 50% of cases, the medicines were sold loose, without the original primary packaging, into little plastic bags with the name of the active ingredient, the strength, the expiry date and, only in some cases, the producer name and country written by pen. In 25% of the analysed samples the expiry date was not available. Moreover, the storage conditions reported in the form were inadequate (open stall, without protection from sun, hand bags).
Analytical results of the antimalarial samples purchased from the informal market in Congo, Burundi and Angola.
% Assay (%RSD)
Uniformity of Mass
% Dissolved4 (%RSD)
In the "Essential Drugs Programme-WHO" pot/02-2007
75 (5) OOS
88.6 (0.6) OOS
58 (7) OOS
72.3 (0.6) OOS
30 (8) OOS
in blister and secondary packaging/08-2008
50 (5) OOS
in blister and secondary packaging/08-2007
in blister and secondary packaging/08-2007
26 (3) OOS
75 (7) OOS
% Dissolved 5 (%RSD)
S = 94.8 (0.6)
S = 79.5 (0.2)
P = 99.1 (0.1)
P = 73 (2)
in blister and secondary packaging/06-2007
S = 96.3 (0.3)
S = 97 (5)
P = 100.3 (0.2)
P = 67.9 (0.6)
in blister and secondary packaging/02-2007
S = 98 (1)
S = 99 (1)
P = 100.9 (0.6)
P = 72 (1)
S = 95.9 (0.6)
S = 95 (3)
P = 97.9 (0.4)
P = 73 (3)
S = 94.0 (0.2)
S = 57 (3) OOS
P = 94.1 (0.6)
P = 24 (1) OOS
in blister and secondary packaging/06-2007
S = 96 (1)
S = 84 (3)
P = 102.7 (0.1)
P = 52 (2) OOS
S = 93.3 (0.4)
S = 80.6 (0.7)
P = 104.6 (0.6)
P = 53 (7) OOS
S = 95 (1)
S = 72 (1)
P = 100.7 (0.9)
P = 45 (3) OOS
S = 97.3 (0.2)
S = 95 (1)
P = 100.8 (0.5)
P = 55 (5)OOS
S = 93.8 (0.4)
S = 47 (2)OOS
P = 99.1 (0.8)
P = 18.6 (0.6)OOS
The results obtained from the analysed samples show three different kinds of problems: (i) the presence of a low quantity of active substance, observed in one sample; (ii) the substitution of an active substance by a different one, observed in one sample, and (iii) the OOS results concerning the dissolution profile, a parameter that correlates with bioavailability. This kind of OOS was observed in 13 samples out of 28 (46% of cases). Moreover, the high RSD% values observed in some dissolution tests indicate a large variability in the production process, that is non-controlled and non-"Good Manufacturing Practices". The dissolution test is a technological test not usually performed in the quality control of samples from developing countries market. The results reported here indicate that in many cases even samples containing the right quantity of active substance could do not show the same therapeutic properties in terms of bioavailability. In fact, assuming a medicine with a very high or very low absorption rate in the body in comparison with the branded medicine for which in vivo efficacy was demonstrated, could affect the good result of therapy. The change in excipients could dramatically affect the in vivo efficacy if a bioequivalence study or, at least, an in vitro study such as the dissolution test was not performed. Moreover, the OOS results were obtained for pyrimethamine probably because of its poor solubility in water. This argument will be investigated for other life-saving medicines containing low water-soluble active substances marketed in developing countries. Generally, counterfeits and sub-standards are considered an economic and health problem mainly owing to lower strength, absence of active substance or presence of a different active. The results here reported evidenced as the legal or illegal production in developing countries could also involve problems of bioavailability and bioequivalence of medicinal products. When bioequivalence studies are not performed, the assumption that a drug with the right content of active substance is "in standard" is not always correct, especially with low soluble actives. In these cases, the health professional should consider that the therapeutic response could be very different from that expected.
This research was carried out in collaboration with and supported by a grant of the Italian Medicines Agency (AIFA).
The Authors thank the Italian NGO VIS, Dr. Mariangela Agus, Dr. Giuseppe Guglielmi and Dr. Eugenio Marchetti for their help in obtaining the antimalarial drugs from the African market.
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