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NDT Advance Access originally published online on October 11, 2006
Nephrology Dialysis Transplantation 2007 22(2):605-611; doi:10.1093/ndt/gfl569
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Drugs as a hidden source of aluminium for chronic renal patients

Denise Bohrer1, Denise C. Bertagnolli1, Sandra M. R. de Oliveira1, Paulo C. do Nascimento1, Leandro M. de Carvalho1 and Solange G. Pomblum2

1Department of Chemistry, 2Department of Toxicology, Federal University of Santa Maria, 97110-905 Santa Maria, RS, Brazil

Correspondence and offprint requests to: Denise Bohrer, Chemistry Department, Federal University of Santa Maria, 97110-905 Santa Maria, RS, Brazil. Email: ndenise{at}quimica.ufsm.br

Keywords: aluminium; contamination; drugs; impurity; renal insufficiency



   Introduction
Top
 Introduction
Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Chronic aluminium exposure and toxicity related to aluminium absorption continue to be a problem for many patients with renal failure [1]. The two most prevalent sources of aluminium are water used to prepare dialysate and aluminium-containing phosphate binders. However, calcium-based binders, Sevelamer or others, have replaced aluminium phosphate binders and reverse osmosis has been used for water treatment in almost all haemodialysis centres [2–4].

In spite of the reduced exposure of patients to aluminium through these sources, patients on regular renal dialysis present abnormal plasma/serum aluminium levels [5]. In the United Kingdom [6], plasma aluminium was audited over the period of January 2000 to January 2004, resulting in a collection of results for 1626 patients. The range was 1.9–817 µg/l, with a mean value of 12.7 µg/l. In the United States, a survey examined retrospectively 1410 measurements of serum aluminium from January 2000 through April 2003 [7]. Although aluminium serum values were satisfactory considering the evolution of the treatment conditions, they cannot be considered within the normal range for all patients, below 15 g/l [7–10].

Patients with renal insufficiency are often on multiple medication. From 80 to 90% of individuals with chronic kidney disease have problems with high blood pressure at some time during the disease. Medicines are used to keep blood pressure in a safe range and to slow the progression of kidney damage caused by this disturbance. Erythropoietin (Epo) and iron supplementation may be used to treat anaemia, which frequently occurs in certain chronic kidney diseases. Specific medications are sometimes needed to treat imbalances of electrolytes, such as high potassium, high phosphate and low calcium levels. Diuretics are also frequently used to treat fluid build-up caused by chronic kidney diseases. Patients on haemodialysis often receive medication for heart failure.

Although complying with pharmacopoeias’ prescription related to quality, drugs may have aluminium as impurity and therefore be an extra aluminium source for the patients. Moreover, most formulations contain not only active ingredients but also additives, excipients and vehicles, used to dilute or aggregate the preparation. Certain products can inadvertently contain aluminium in its formulation. Talcum, a common excipient, may present an elevated amount of aluminium, since aluminium oxide can be one of its constituents.

In this study we investigated whether the medicines taken by patients on haemodialysis treatment can be an aluminium source. Commercial products, active ingredients and all other substances that comprise these formulations were analysed for their aluminium content.



   Materials and methods
Top
 Introduction
 Materials and methods
Results
 Discussion
 Acknowledgements
 References
 
Apparatus
A Varian SpectrAA-200 atomic absorption spectrometer equipped with a GTA-100 graphite furnace and an auto sampler (Melbourne, Australia), a Trox class 100 clean bench (Curitiba, Brazil), a domestic microwave oven (Philips, São Paulo, Brazil) and a Berghof BSB 939-IR sub-boiling distillation apparatus (Eningen, Germany) were used.

Reagents
The water used throughout was distilled, deionized and further purified by a Milli-Q high purity water device (Millipore, Bedford, USA). An aluminium standard solution containing 1000 mg/l Al (Merck, Germany) was used to prepare the working standard solutions. HNO3 [65% (m/m), 1.17 g/ml] from Merck was further purified by sub-boiling distillation.

Contamination control
To avoid contamination, only plastic materials were used. All laboratory ware (pipette tips, volumetric flasks, etc.) was immersed for at least 48 h in a 10% (v/v) HNO3/ethanol solution and shortly before, was washed with Milli-Q purified water. To avoid contamination from the air, all steps in the sample and reagents preparation were carried out in a class 100 clean bench.

Procedures
Analysis of raw materials
Raw materials included four groups: active ingredients, vehicles, lubricants and diluents. For the analysis, the substances were solubilized according to pharmacopoeias’ monographs [11,12] or after establishing the best solvent or decomposition procedure (described subsequently) to each one. Heparin was dissolved in water to give a solution with the same UI/ml (5000) of the commercial product. After dissolution and dilution in polyethylene volumetric flasks, the aluminium content of each sample was measured by flame or electrothermal atomic absorption spectrometry (FAAS or ETAAS, respectively), following the conditions described in Table 1. At least three different samples of each substance were assayed, and the reported results correspond to the mean value.


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  		Table 1. Flame and graphite furnace operation conditions

 
Gelatinous capsules
Capsules were dissolved in 5 ml of 0.1 mol/l HNO3 and the volume was completed to 10 ml with water.

Starch and lactose
40 ml water was added to 0.5 g of the sample and the mixture was heated for 30 min. After cooling down, the volume was completed to 50 ml with water.

Talcum, stearic acid and magnesium stearate
To 0.5 g sample 20 ml of 10% triton X-100 solution was added. The mixture was a suspension stable enough to be aspirated into the flame of the spectrometer. Just before the measurement, the suspension was well-homogenized.

Microcrystalline cellulose
0.5 g of the sample was dissolved with 20 ml of 1.5% (m/v) NaOH solution.

Analysis of commercial products
Aluminium in commercial products was measured by FAAS or ETAAS after adequate dissolution or decomposition. For all products, at least three samples of the same batch were analysed, and the reported results correspond to the mean value.

Procedures for sample decomposition
Water, ethanol, methanol as well as acetonitrile and inorganic acids were tested for dissolution of samples. Samples not soluble in water or organic solvents were dissolved in pure concentrated nitric acid or in its mixture with concentrated hydrochloric acid (1:3).



   Results
Top
 Introduction
 Materials and methods
 Results
Discussion
 Acknowledgements
 References
 
Determinations by conventional atomic absorption spectrometry require samples in the form of a solution or a suspension. The liquid sample is aspirated into a flame or pipetted into a graphite tube to be atomized and the element determined. Several samples analysed in this study are insoluble or scarcely soluble in common solvents like water or ethanol. Solubilization of raw materials was carried out in accordance with pharmacopoeias’ monographs [11,12], when available, or was obtained following one of the aforementioned methods. Pharmacopoeias’ procedures were followed only when they were not incompatible with the AAS technique.

Table 2 presents the aluminium content of the analysed raw materials. The aluminium level found in raw substances is, in most of them, low and within the limit prescribed by pharmacopoeias. Exceptions were magnesium stearate, microcrystalline cellulose and talcum. Among them, magnesium stearate is the most contaminated, presenting almost 40 µg/g aluminium. Talcum, used as excipient, may have aluminium among its constituents; one of the investigated products was labelled to contain 1.5% (m/m) aluminium oxide ({cong}7900 µg/g Al). The other, supposedly not containing aluminium, showed an aluminium level equally high, though in agreement with pharmacopoeias’ limit (<2% Al) [11,12].


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  		Table 2. Aluminium present as contaminant in raw materials

 
Solid formulations for oral use are commercialized in the form of pills, tablets or capsules. In general, pills and tablets are obtained by compressing the active ingredient along with sugar, sorbitol, gelatine or starch. For medicines in the form of capsules, on the other hand, the active ingredient is stored in a solid, soluble wrapper, made either of soft or hard gelatine. Sugar, sorbitol, gelatine and starch as individual substances were analysed in this study along with the excipients, and their aluminium content is presented in Table 1. Since capsules are individual identities, made especially to be a pharmaceutical form to wrap oral drugs, empty capsules were analysed separately. Because they are commercialized in different colours, capsules of 15 different colours were analysed. The results showed, however, that there is no statistical difference between coloured (Al range from 0.19 ± 0.03 to 0.80 ± 0.07 µg/capsule) and colourless capsules (Al range from 0.61 ± 0.01 to 0.82 ± 0.08 µg/capsule). The only one that should be mentioned is one sample of blue capsules, in which the aluminium level was two times higher than the level in the colourless ones. However, since among blue colour additives allowed to be used in drugs [13], no one contains aluminium in its composition, contamination probably had an environmental source.

Table 3 lists the commercial medicines classified in accordance with their pharmaceutical form. While in most solid products (capsules and tablets) the aluminium level was below 1 µg/g, acetylsalicylic acid, calcitriol, clonidine and vitamins of B complex presented levels as high as 85 µg/g. Still higher were the levels in iron sulphate and calcium carbonate samples, over 200 µg/g.


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  		Table 3. Aluminium present as contaminant in commercial products

 
All liquid formulations presented aluminium as impurity. The least contaminated was the albumin sample, 0.24 ± 12.0 µg/ml. Among heparin and Epo samples the aluminium level varied from 0.19 to 0.82 µg/ml, with the exception of one Epo sample, containing 1.94 ± 0.4 µg/ml. More surprising are the levels found in dypirone and injectable iron, 11.27 ± 7.5 µg/ml and 32.61 ± 8.7 µg/ml, respectively. If one considers the administration of a typical 1000 mg elemental iron dosage for haemodialysis patients, which corresponds to 50 ml of the analysed iron formulation (20 mg iron per ml), at least 1630 µg aluminium would be taken by the patient at once.

In Figure 1, the aluminium level found in active substances and in the respective commercial products is compared. The graphics show that all commercial products contain more aluminium than the active substances. Although it might be related to the manufacturing process, where the formulation could come in contact with any aluminium source, the origin of the higher aluminium level seems to be related to the additives. Table 4 presents the composition of each commercial product. While in solid products with small number of additives the aluminium contamination tends to be low, in others like vitamins of B complex and acetylsalicylic acid, which contain among others, talcum, aluminium contamination is very high (Figure 1A). On the other hand, in products like digoxin, enalapril and propanolol, the additives did not contribute to elevation of the aluminium contamination. Among injectable drugs, the commercial products contain much more aluminium than the pure active substances (Figure 1B). Again, the additives may have contributed to the elevation of the aluminium level in these products.


Figure 1
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  		Fig. 1. Comparison between the aluminium that would be present in a product considering only the impurity in the raw material and the contamination found in the commercial product [the Al level in calcium carbonate (mean value), ferrous sulphate, dipyrone and iron sucrose exceeds the axis scales]. The axis scales were chosen in order to distinguish the Al level in all products. (A) Solid formulations; (B) liquid formulations.

 

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  		Table 4. Composition of commercial formulations

 


   Discussion
Top
 Introduction
 Materials and methods
 Results
 Discussion
Acknowledgements
 References
 
Aluminium is present as an impurity in raw substances used to manufacture medicines usually consumed by chronic renal patients. Raw materials have guarantee bulletins certifying their purity grade. There are, however, no limits for aluminium in these specifications. Metal contamination limits in substances of pharmacopoeial grade are generally treated as limits for ‘heavy metals’, which probably include elements such as lead, cadmium, zinc or copper. Limits for heavy metals or aluminium, when existing, vary from 1 to 50 µg/g, depending on the substance and manufacturer. Since these products are not specifically destined to manufacture medicines for patients with chronic renal failure, the presence of aluminium is not taken into consideration.

Actually, aluminium is not considered a relevant toxic species for most environments. Considering that aluminium salts find use in fields such as water treatment, glass industry and bakery, it is not surprising that it is not considered a harmful impurity. The presence of aluminium in foodstuff was reviewed by Yokel [14]. While natural diets are likely to contain little aluminium, diet containing either processed or cooked foods may contain more. He commented that aluminium-based baking powders may contain more than 10 mg/g Al, and bread or cake made with these may contain 5–15 mg of the element per slice.

Among all investigated products, iron and calcium formulations presented significant contamination by aluminium. If one considers that both cations present chemical properties similar to aluminium, it is reasonable to accept aluminium as a natural impurity in iron and calcium compounds.

Aluminium is also present in commercial formulations. Since the contamination in commercial formulations is higher than in the respective raw materials, it might be attributed to the manufacturing process. It should, however, arise from additives much more than from any step of the processing. Among additives, there are some that present elevated affinity for aluminium [15], and therefore may be responsible for carrying it into the formulations. Phosphate and citric acid are well-known complexing agents for aluminium. Studies of the bioavailability of ingested aluminium indicate that the co-administration of citrate and other chelating molecules (e.g. lactate and ascorbate) increases its absorption [16].

Another source of aluminium for commercial formulations is the container. Since all liquid formulations are stored in glass containers, and glass contains aluminium in its constitution, the additives, which present an affinity for aluminium, may cause it to migrate from the container into the solution [17].

Aluminium exposure in chronic kidney disease is a well-recognized problem and most exposure is felt to be avoided through the use of reverse-osmosis and avoidance of aluminium-containing phosphate binders. However, medication may provide a hidden source of unacceptable amounts of aluminium to these patients.

Excipients such as magnesium stearate, microcrystalline cellulose and mainly talcum that contain high aluminium levels should be avoided in products destined for chronic renal patients. Additionally, additives such as citric acid, which presents elevated affinity for aluminium, should also be avoided since they may increase aluminium absorption.

Great attention should be paid to the presence of aluminium in injectable drugs because of the way they are administered. The high aluminium level found in these formulations enters directly into the blood stream of the patients, facing no barriers.

It would be advisable that products destined for chronic renal patients have their composition re-evaluated in order to contain only components with reduced aluminium contamination.



   Acknowledgements
Top
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors are grateful to Fapergs (Fundação de Amparo à Pesquisa do RS, Brazil) for the financial support.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. Ruster M, Abendroth K, Lehmann G, Stein G. (2002) Aluminum deposition in the bone of patients with chronic renal failure—detection of aluminum accumulation without signs of aluminum toxicity in bone using acid solochrome azurine. Clin Nephrol 58:305–312.[Web of Science][Medline]
  2. Persy VP, Behets GJ, Bervoets AR, De Broe ME, D’Haese PC. (2006) Lanthanum: a safe phosphate binder. Semin Dial 19:195–199.[CrossRef][Web of Science][Medline]
  3. Storms LE, Chicella MF, Dice JE. (2006) Sevelamer therapy for pediatric end-stage renal disease. Pharmacotherapy 6:410–413.[CrossRef]
  4. Coladonato JA. (2005) Control of hyperphosphatemia among patients with ESRD. J Am Soc Nephrol 16:Suppl 2, S107–S114.[Abstract/Free Full Text]
  5. Kausz AT, Antonsen JE, Hercz G, et al. (1999) Screening plasma aluminum levels in relation to aluminum bone disease among asymptomatic dialysis patients. Am J Kidney Dis 34:688–693.[Web of Science][Medline]
  6. Gault PM, Allen KR, Newton KE. (2006) Plasma aluminium: still necessary for patients on renal dialysis? Ann Clin Biochem 43:51–54.
  7. Jaffe JA, Liftman C, Glickman JD. (2005) Frequency of elevated serum aluminium levels in adult dialysis patients. Am J Kidney Dis 46:316–319.[CrossRef][Web of Science][Medline]
  8. Diagnosis and treatment of aluminium overload in end-stage renal failure patients. Nephrol Dial Transplant (1993) 8:Suppl 1, pp. 1–4.[Medline]
  9. Eichhorn GL. (1993) Is there any relationship between aluminum and Alzheimer's disease? Exp Gerontol 28:493–498.[CrossRef][Web of Science][Medline]
  10. Gonzalez EA, Kevin J, Martin KL. (1992) Aluminum and renal osteodystrophy. A diminishing clinical problem. Trends Endocrin Met 3:371–375.[Medline]
  11. USP 27 United States Pharmacopoeia. (2005).
  12. British Pharmacopoeia. (2003) version 7.0 Data © Crown, volumes I and II.
  13. Schoneker DR. (2002) Coloring agents for use in pharmaceuticals. In Swarbrick J and Boylan JC (Eds.). Encyclopedia of Pharmaceutical Technology(Dekker, New York, USA) pp. 509–530.
  14. Yokel RA. (2004) Aluminum. In Merian E, Anke M, Inhat M, Stoeppler M (Eds.). Elements and their Compounds in the Environment 2nd edn. (Wiley-VCH, Weinheim, Germany) pp. 635–658.
  15. Bohrer D, do Nascimento PC, Martins P, Binotto R. (2002) Availability of aluminum from glass and an Al-form ion exchanger in the presence of complexing agents and amino acids. Anal Chim Acta 459:267–276.[CrossRef]
  16. Weberg R and Berstad A. (1986) Gastrointestinal absorption of aluminium from single doses of aluminium containing antacids in man. Eur J Cin Invest 16:428–432.
  17. Bohrer D, do Nascimento PC, Binotto R, Becker E. (2003) Influence of the glass packing on the contamination of pharmaceutical products by aluminium. Part III: interaction container-chemicals during heating for sterilisation. J Trace Elements Med Biol 17:107–115.[CrossRef][Web of Science][Medline]
  18. Bohrer D, do Nascimento PC, Binotto R, Becker E, Pomblum S. (2002) Contribution of the raw material to the aluminium contamination in parentesal. J Parentes Entesal Nutr 26:383–388.
Received for publication: 12. 6.06
Accepted in revised form: 27. 8.06


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Home page
 Nephrol Dial TransplantHome page
D. Bohrer, D. C. Bertagnolli, S. M. R. de Oliveira, P. C. do Nascimento, L. M. de Carvalho, S. C. Garcia, L. C. Arantes, and E. J. G. Barros
Role of medication in the level of aluminium in the blood of chronic haemodialysis patients
Nephrol. Dial. Transplant., April 1, 2009; 24(4): 1277 - 1281.
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