Table of Contents  

Jacob, Shirwaikar, Anoop, Khaled, Imtiaz, and Nair: Acid neutralization capacity and cost-effectiveness of antacids sold in various retail pharmacies in the United Arab Emirates

Introduction

Antacids are the mainstay of gastric ulcer therapy. Several controlled studies have established their efficacy in ameliorating peptic and duodenal ulceration.1,2 Drugs that are more effective than antacids in healing ulcers and relieving the symptoms of gastro-oesophageal reflux are available, but many people still use over-the-counter antacids to treat dyspepsia and heartburn.36 Despite competition from new H2-receptor blockers, antacids are still prescribed in large quantities. Current annual expenditure on over-the-counter antacid and indigestion products in the USA alone exceeds $1.2 billion.7 Proton pump inhibitors (PPIs), which include esomeprazole (Nexium®, AstraZeneca UK Ltd), lansoprazole, omeprazole, pantoprazole and rabeprazole (Pariet®, Eisai),8 as a class, are the most potent inhibitors of gastric acid secretion. PPIs are inactivated by gastric acid and, thus, are generally administered as enteric-coated tablets or capsules. Many antacid preparations are available on the market, and are often reformulated by the manufacturers. As a result, physicians and the public are often bewildered by the wide choice of over-the-counter preparations and the conflicting advertisements extolling the merits of one preparation over another.

Ideally, a prescribing physician should take the following into consideration when choosing an antacid preparation:

  • It should have high acid-neutralizing capacity (ANC) (expressed in milliequivalents).

  • It should neutralize the greatest volume of acid per unit cost.

  • It should be both palatable and easy to consume.

Other factors that should be considered include the sodium content of the antacid, the calorific content, the constipating or diarrhoeagenic effects, the physical form (tablet or liquid) and the cost to the pharmacist.9

Antacids are frequently used, self-prescribed, over-the-counter medication. They consist of calcium carbonate and different forms and combinations of magnesium and aluminium salts. The action of antacids on the stomach is a result of the active neutralization of gastric HCl and the inhibition of pepsin.10 The ANC of an antacid is a measure of the ability of the antacid tablet or liquid formulation to neutralize stomach acid at a temperature of 37°C ± 2°C, and is expressed in milliequivalents. Typically, higher doses of antacids are required to notably elevate gastric pH, and the ANC of antacid preparations may vary widely between different brands. As the effectiveness of antacid preparations is based on the ANC, the cost of the antacid preparation should ideally be based on target neutralizing capacity.

Globally, the past 10 years has witnessed many changes in antacid formulations.11 Although the variability in ANC of the antacid formulations has reduced from a sevenfold difference in the 1970s to a threefold difference in the 1980s, no study has been carried in the United Arab Emirates (UAE) to evaluate the neutralization capacity of currently marketed antacid formulations. As the efficacy of antacids is associated with the ANC, it is essential to differentiate presently marketed antacid products. It is also noteworthy that the antacid product labels do not include any data on the ANC. Antacid preparations contain active ingredients, excipients, flavouring and sweetening agents; as a result, they may contain considerable volumes of sodium and have a high calorie content. Thus, it is important that patients suffering from conditions such as hypertension, renal impairment or diabetes choose, or are prescribed, an antacid formulation that is lower in sodium and calories.12

Our aims were to determine and verify the ANC of antacid preparations sold in various retail pharmacies in the UAE and to quantify the volume of sodium and the calorific content of various antacid preparations from different manufacturers, as well as overall monthly consumption and cost of therapy. We evaluated the monthly dose equivalent to a target neutralizing capacity of 140 mEq as well as the monthly cost of therapy.

Materials

We purchased 10 solid and five liquid antacids from community pharmacies in the Ajman area of UAE. We also used hydrochloric acid (Nice Chemicals Private Limited, Kochi, India), a magnetic stirrer and a pH-meter (Remi, Mumbai, India).

Methods

In vitro acid-neutralizing capacity

Determination of ANC was determined in accordance with United States Pharmacopeia (USP) 30 and the National Formulary (NF) 25.13,14 In short, all tests were conducted at a temperature of 37°C ± 2°C. A pH-meter was standardized using potassium biphthalate and potassium tetraoxalate (0.05 M each) and standardized buffers. A magnetic stirrer was used to maintain a stirring rate of 300 ± 30 rpm The average tablet weight was determined from 20 tablets. The tablets were reduced to a fine powder and an accurate weight, equal to the minimum dose, was transferred to a 250 ml beaker, to which we added 5 ml of alcohol, followed by mixing. Following addition of 70 ml7 of water in the case of non-chewable tablets (or 50 ml in the case of chewable tablets), the sample was again mixed using a magnetic stirrer for 1 minute. Hydrochloric acid (1 N, 30 ml) was then added and the sample stirred for a further 15 minutes. Titration was carried out immediately to determine excess HCl using 0.5 N NaOH to attain a stable pH of 3.5. The volume of acid used (in milliequivalents) was calculated using the equation:

Total mEq = ( 30 × N HCI ) ( V NaOH × N NaOH )

where NHCl and NNaOH is the normality of HCl and NaOH, respectively, and VNaOH is the volume of NaOH used for titration. The results were expressed as total milliequivalents per gram of substance (USP). Sodium and calorie content of the antacids were received from the manufacturers. All tests were analysed in triplicate with the ‘USP-XX-NF-XV’ acid neutralization test.

Results

Tablet antacids

We were unable to obtain samples from different manufacturing lots of the 10 tablet antacids tested. The results of analysis of variance (ANOVA) of ANC are shown in Table 1. The standard deviation (SD) for the within-lot replication failure was estimated as 0.42. The tablet antacids can be classified into three ANC groups (Figure 1 and Table 2). Three (H-1, H-2, H-3) have an ANC that conforms to those of liquid antacids in the high group. The data show that the ANC of the three tablet antacids with the lowest ANC is higher than the ANC of other seven antacid tablets as long as the SD of the lot-to-lot variation does not exceed 2.35.

TABLE 1

ANOVA of 10 tablet antacids (ANCs), each estimated in triplicate and in four different production lots prepared by different runs

Variable Degrees of freedom Mean square F
Tablet 9 65.800 659
Error 12 0.118
FIGURE 1

Classification of tablet antacids.

9-2-2-fig1.jpg
TABLE 2

Attributes of 10 solid antacids

ANC group and product Ingredients ANC (mEq/tablet) Sodium content (mg/tablet) Calorie content (mg/tablet) Average price per one strip (10 tablets) (AED)
High
H-1 Al(OH)3 – 200 mg
Mg(OH)2 – 200 mg
34.88 0.9 2.8 4.38
H-2 CaCO3 – 500 mg 31.74 0 0 4.29
H-3 Al(OH)3 – 200 mg
Mg(OH)2 – 200 mg
33.00 1.2 2.4 2.00
H-4 CaCO3 – 1000 mg 31.27 0 5 4.50
Intermediate/high
IH-1 Al(OH)3 – 160 mg
Mg(OH)2 – 105 mg
29.65 0.8 2.5 8.13
IH-2 Al(OH)3 – 680 mg
MgCO3 – 80 mg
26.97 14.0 1.5 1.80
Intermediate
I-1 Al(OH)3 – 405 mg
Mg(OH)2 – 100 mg
20.12 1.2 2 2.00
Low
L-1 Al(OH)3 – 225 mg
Mg(OH)2 – 200 mg
18.89 15.42 2.5 1.50
L-2 Al(OH)3 – 250 mg
Magnesium trisilicate – 120 mg
Mg(OH)2 – 120 mg
19.13 5 2.4 1.60
L-3 Al(OH)3 – 225 mg
Mg(OH)2 – 200 mg
19.42 1.4 2.4 1.80

Sodium and calorie content and the cost to pharmacists and/or the public

The sodium and calorie content and price to the pharmacist of the antacids we tested are given in Table 2.

Liquid antacids

The five liquid antacids tested were analysed for ANC within the lot for reproducibility (Figure 2). Only two (LH-1 and LH-2) were found to have high ANC between four lots at the 5% level of significance. The ANOVA of five products is shown in Tables 3 and 4. Liquid antacids are classified into five statistically different groups based on ANC (Table 5 and Figure 2). No groups had shown a correlation between ANC and the total volume of antacid ingredients. From statistical analysis, we estimated lot–lot error = 0.92, single observation error = 0.95 and lot mean error = 0.93 (SD 0.23).

FIGURE 2

Classification of liquid antacids.

9-2-2-fig2.jpg
TABLE 3

The ANOVA of five liquid antacids (ANCs), each estimated in triplicate and in five lots

Variable Degrees of freedom Mean square F
Liquid 4 65.8000 143
Lots 10 1.5600 23
Error 98 0.0231
TABLE 4

The ANOVA of five liquid antacids (lot average ANCs)

Variable Degrees of freedom Mean square F
Liquids lot means 12 65.40 112
Error 23 0.80
TABLE 5

Attributes of five liquid antacids

ANC group and product Ingredients (5 ml) ANC (mEq/5 ml) Sodium content (mg/5 ml) Calorie content (mg/5 ml) Average price per 10 ml (AED)
High
LH-1 Al(OH)3 – 225 mg 35.83 1.4 1.6 0.50
Mg(OH)2 – 200 mg
LH-2 Al(OH)3 – 215 mg 35.92 0.9 2.2 0.55
Mg(OH)2 – 80 mg
Intermediate/high
LIH-1 Sodium alginate – 250 mg 30.26 1.1 1.4 0.55
Sodium bicarbonate – 133.5 mg
CaCO3 – 80 mg
Intermediate
LI-1 Al(OH)3 – 405 mg 20.22 1.2 2.2 0.48
Mg(OH)2 – 100 mg
Low
LL-1 Al(OH)3 – 250 mg 18.22 5.0 2.4 1.00
Magnesium trisilicate – 120 mg
Mg(OH)2 – 120 mg

Discussion

The ANC of the most effective liquid antacid analysed was twice that of the least effective. None of the product labels of antacids from any manufacturer mentioned either the absolute or relative neutralizing capacity of the product. Most companies advocate a regular dose of one or two teaspoons (5–10 ml) of antacid, regardless of the ANC. Depending on the particular product, this dose will neutralize 18.22–35.83 mEq (5 ml) or 36.44–71.66 mEq (10 ml) of acid. Owing to this large deviation in neutralizing capability, the brand and dose must be established when antacid administration is being suggested or recommended.

There was no statistically significant difference in the ANC of the three groups of liquid antacids tested. Table 6 and Figure 3 show the average single dose necessary to neutralize 80 mEq and 144 mEq of acid. The doses selected represent maximum low/high doses of an antacid regimen. Table 6 and Figure 3 show that maximum acid neutralization combined with the lowest dose volume–weight ratio is achieved by high-ANC or intermediate/high-ANC (liquid and tablet) antacids. The consumption of these antacids also minimizes sodium and calorie intake and cost to the pharmacist. It is necessary to investigate sodium and calorie content before selecting an antacid product for those patients whose sodium and calorie intake needs to be restricted.

TABLE 6

Comparative evaluation of liquid/solid antacids belonging to different ANC groups

ANC group Product Single dose tablet/volume (ml)/day Daily sodium intake (mg) Daily calorie intake (mg) Price pharmacist (AED) Monthly cost of high-dose therapy (AED)
80 mEq 144 mEq 80 mEq 144 mEq 80 mEq 144 mEq 80 mEq 144 mEq
ANC group: tablet
High H-1 3 tablets 5 tablets 2.7 4.5 2.0 3.6 1.31 2.19 65.70
H-2 3 tablets 5 tablets NA NA NA NA 1.29 2.15 64.50
H-3 3 tablets 5 tablets 2.4 4.3 2.2 4.0 0.60 1.00 30.00
Intermediate/high IH-1 3 tablets 5 tablets 2.4 4 1.8 3.2 2.44 4.06 121.80
IH-2 3 tablets 6 tablets 1.8 3.2 1.1 1.98 0.55 1.11 33.33
Intermediate I-1 4 tablets 8 tablets 2.4 4.3 1.0 1.2 0.80 1.60 48.00
Low L-1 6 tablets 10 tablets 1.1 2.0 1.6 3.0 0.90 1.50 45.00
ANC group: liquid
High LH-1 3 ml 6 ml 1.8 3.2 2.4 4.3 0.15 0.33 9.90
LH-2 3 ml 6 ml 2.2 4.0 2.4 4.0 0.17 0.33 9.90
Intermediate/high LIH-1 3 ml 6 ml 1.6 2.88 2.0 3.6 0.17 0.33 9.90
Intermediate LI-1 4 ml 7 ml 2.4 4.3 1.0 1.2 0.19 0.34 10.20
Low LL-1 5 ml 9 ml 1.8 3.24 1.5 2.7 0.20 0.90 27.00

NA, not applicable.

FIGURE 3

Solid/liquid antacids: ANC and single dose volume/day.

9-2-2-fig3.jpg

Liquid antacids are preferred to tablet antacids for the treatment of gastric ulcers because they provide a greater surface area, which results in better neutralization capacity.15 Nevertheless, the ANC of three of the tablet antacids we analysed was similar to that of high-ANC liquid antacids, and higher than the ANC of low-ANC liquid antacids. The amount of active ingredient in these tablet antacids is almost identical to the amounts found in high-ANC liquid antacids. In addition, these tablets are designed to dissolve quickly, which is a vital aspect in quantifying the ANC of a tablet.

Tablet antacids are cheap, acceptable, portable and more convenient than liquid antacids and, therefore, are an affordable and feasible substitute for liquid antacids (e.g. when a dose needs to be taken outside a hospital setting). For example, three tablets of H-1, H-2 or H-3 (see Figure 3) are required to achieve an ANC of 80 mEq (low-dose therapy) and five are required to neutralize 144 mEq of HCl (high-dose therapy). It has been suggested that chewable tablet antacids can increase surface area and, therefore, yield superior neutralization capacity.16 All the liquid and tablet antacids tested provided < 1 mEq (23 mg) of sodium ions.

The daily cost of high-dose therapy is much lower for high-ANC tablet antacids than for low-ANC tablet antacids (Figures 4 and 5). As shown in Figure 6, the monthly cost of high-dose therapy of liquid antacids is one-third the cost of the cheapest tablet antacid therapy. Sodium content and calorific value of all currently available commercial antacids were negligible owing to the availability of non-calorific- and non-sodium-containing excipients.

FIGURE 4

Solid antacids: ANC and average daily cost of high-dose therapy.

9-2-2-fig4.jpg
FIGURE 5

Liquid antacids: ANC and average daily cost of high-dose therapy.

9-2-2-fig5.jpg
FIGURE 6

Tablet and liquid antacids: monthly cost (AED) of daily high-dose therapy.

9-2-2-fig6.jpg

Conclusions

When large doses of antacids are recommended for the treatment of gastric ulcers, antacids with a high ANC are the preferred agents. These products combine high neutralization capacity with a low dose volume–weight ratio, low sodium and calorie content, and at the lowest price to the pharmacist and/or the public. Owing to the high neutralization capacity, portability and acceptability, tablet antacids with a high ANC can be substituted for liquid antacids. It is impractical to foresee interlot difference within liquid and tablet antacids, but this may aid in demonstrating an unusual change in the effectiveness of the antacid products. Antacids can be consumed judiciously provided the ANC details are visible on the label of these products.

References

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Department of Health and Human Services. Antacids and antiflatulent drug products for over-the-counter human use; amendment of the monographs. Federal Register 1986; 51:148.

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Brouwers JR, Tygat GN. Biopharmaceutical properties of liquid and tablet antacids: in vivo studies using the intragastric pH-measurement technique. J Pharm Pharmacol 1978; 30:148–51.

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Alderborn G. Tablets and compaction. In: Aulton ME (eds). Aulton’s Pharmaceutics: The Design and Manufacture of Medicines. London, UK: Churchill Livingstone Elsevier; 2007, p. 456.




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