Omeprazole is an acid labile, H+/K+ ATPase inhibitors, also known as proton pump inhibitors, commonly present in either enteric-coated tablets or enteric coated pellets within a capsule. However, in cases such as paediatrics and geriatrics, some patients may experience difficulty in swallowing these solid dosage forms, and therefore, may require a liquid dosage form, such as a dispersion. Dispersions of omeprazole are used in adults for short term treatment of gastroesophageal reflux disease and to decrease the risk of upper gastrointestinal bleeding in critical ill adults. However, can be administered to infants in treating colic via a syringe device.
Omeprazole is generally well tolerated, however, the palatability of the dispersion product needs to be patient acceptable. As omeprazole particles will be evenly dispersed throughout the water, an accurate dose will be each time via a measuring cup or syringe. The higher water content, and decreased viscosity will allow ease in pouring into a measuring cup and drawing up into a syringe. The alkaline pH of the dispersion, used to ensure the stability of omeprazole, may have a bitter taste. This can be overcome by mixing the dose of the dispersion with milk for adults, or breast milk for infants.
Characteristics of Omeprazole:
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Figure 1: Structure of Omeprazole (Martindale, 2010)
Omeprazole is slightly soluble in water, 1 in 1,000 to 10,000 and molecular weight of 345.5 g/mol (BP 2010). Food does not seem to influence the amount of omeprazole absorbed or cause a delay in the absorption (Andersson 1996). The oral bioavailability of the omeprazole capsules is 0.5, which consist of enteric-coated pellets in a hard-gelatin capsule. However, the bioavailability of omeprazole is approximately 50% of that of the capsules, resulting in a bioavailability of 0.25 (Sansom 2009). This low bioavailability is due to omeprazole's acid-labile structure that degrades in the acidic conditions of the stomach rather than it's ability to cross the lipophilic membranes of the gastrointestinal tract.
Omeprazole is sensitive to heat, humidity, light and organic solvents. Therefore, it is suggested that omeprazole formulations are stored between 2°C and 8°C, in an air tight, light-resistant container. Omeprazole has shown to have two absorption maxima at 276 nm and 305 nm (BP, 2010). Molecules, which absorb the wavelengths of light associated with sunlight or artificial light (i.e. 300 400 nm), may be susceptible to photolysis (Aulton, 2007). Discolouration ranging from light beige to deep purple will occur immediately when omeprazole is exposed to these unfavourable conditions.
The biggest contributing factor of omeprazole's stability is the pH of it's environment. The methoxy group of omeprazole is not in direct resonance with the nitrogens of the benzimidazole structure. Due to the electron withdrawing effect of the methoxy group, the basicity of the nitrogen in the benzimidazole structure is reduced (the lone pair of electrons are less available for H+ donation). The degradation of omeprazole is dependent on the protonation of the benzimidazole nitrogen, as protonation of this nitrogen is required for the nucleophilic attack of the nitrogen in the pyridine structure. This protonation of the benzimidazole nitrogen is the rate-limiting step in the degradation of omeprazole. Hence, why omeprazole is slightly more stable than lansoprazole (another proton pump inhibitor) due to the absence of a substituent on the benzimidazole structure, and therefore no electron withdrawing effect that reduces the basicity of the nitrogen (Tutunji et. al. 2006).
Figure 2: Acid degradation of Omeprazole
(Extracted from Tutunji, M, Qaisi A, El-Eswed B, Tutunji L 2006, 'An in vitro investigation on acid catalysed reactions of proton pump inhibitors in the absence of an electrophile,' International Journal of Pharmaceutics, vol. 323 nos 110-116, pp 111.)
Because the protonation of the benzimidazole nitrogen is the rate-limiting step in the degradation of omeprazole (Tutunji et. al. 2006), the extent of how it limits the rate will be highly dependent on the H+ concentration in the surrounding environment. Therefore, at low pH environments where the H+ concentration is high, even at pH 6, there is a large extent of acid degradation of the omeprazole structure compared to a pH 9 environment, where omeprazole is most stable.
pH and its effect on the preservative and omeprazole:
Omeprazole is a weak base with a pKa of approximately 4 (Tutunji et. al. 2006). In conditions where the pH is less than 4, the nitrogen in the benzimidazole ring becomes protonated and omeprazole is ionised. However, rather than increasing aqueous solubility, the omeprazole structure undergoes acid degradation to form larger omeprazole dimer structures. In conditions where the pH is greater than 4, or in even more basic conditions such as pH 9, the omeprazole structure remains unionised and the lone pair of electrons on the nitrogen in the benzimidazole ring are free to hydrogen bond with water molecules, allowing omeprazole to dissolve into solution and preserving its structure.
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Propylparaben and methylparaben exhibit antimicrobial activity between pH 4 and 8. Preservative efficacy decreases with increasing pH owing to the formation of the phenolate anion. The phenol structure is a weak acid with a pKa of approximately 10. With pH's above the pKa value, the hydroxyl functional group becomes ionised.
Figure 3: Propylparaben (Rowe et. al. 2009)
Figure 4: Methylparaben (Rowe et. al. 2009)
Also, at pH environments greater than 8, propylparaben and methylparaben solutions are subject to rapid hydrolysis leading the formation of p-hydroxybenzoic acid, which practically has no preservative activity.
Use of Excipients:
Effect of Excipients in Probitor Capsules (20 mg):
Table 1: Original Dosage Form Excipients (MIMS 2010)
Excipient in Original Dosage Form
Effect of Excipient in Original Dosage Form
Sodium Lauryl Sulfate
Anionic surfactant and capsule lubricant (Rowe, et al. 2009). It is a detergent and wetting agent effective in both alkaline and acidic conditions.
Dibasic Anhydrous Sodium Phosphate
Buffering agent with a pH of 9.1 for a 1% w/v aqueous solution (Rowe et. al. 2009).
Tablet binder, in film coating, and as a matrix for the use in extended release tablet formulations. Suspending or thickening agent in oral liquid dosage forms.
Primariliy used as a diluent in tablet formulations. Is not hygroscopic and therefore, can be used with moisture-sensitive active ingredients. Used in wet granulations as granulations containing mannitol have the advantage of being dried easily.
Capsule lubricant and diluent.
Coating agent and white pigment.
Eudragit L30-D-55 (ARTG no. 3700)
Plasticiser for creating an enteric coat for each pellet, that can be used when compressing pellets into tablets without significant damage.
Diluent and lubricant. Does not gelatinise on exposure to moisture or steam sterilisation.
Binding agent for wet granulation.
As omeprazole is very slightly soluble in water, all excipients from original dosage form cannot be filtered out and hence, will remain in the dispersion.
May cause sensitization by skin contact and therefore, safety glasses, gloves and protective clothing are recommended. Avoid storage with oxidising agents by storing in the original containers and keep the containers securely sealed.
May produce discomfort of the eyes and skin, therefore, it is recommended to avoid contact with skin and wear eye and face protection. In the case of contact with the eyes, rinse with plenty of water.
Compound Hydroxybenzoate Solution APF
Although they have been used in injection and ophthalmic preparations, there are now considered inappropriate due to irritation caused by the benzoates such as propylparaben and methylparaben. Hypersensitivity reactions caused by the benzoates are typically delayed and appear as contact dermatitis at the injection site, however can occur after ingesting an oral preparation. As it may be irritant to the eyes and skin, during production or when handling, eye protection, gloves and appropriate clothing are required (Rowe et. al. 2009).
Table 2: Safety of the Excipients from the Original Dosage Form (Rowe et. al. 2009)
Excipient in Original Dosage Form
Sodium Lauryl Sulfate
Safety glasses, gloves and protective clothing are recommended when handling as it emits toxic fumes on combustion. It is stable under normal storage conditions (temperature at 25°C, and in a cool, dry place), however, in solution under extreme conditions, such as a pH of 2.5, sodium lauryl sulfate undergoes hydrolysis.
Dibasic Anhydrous Sodium Phosphate
Considered to be a safe excipient in oral formulations as phosphate occurs extensively throughout the body and is involved in many physiological processes.
Generally regarded as a non-toxic and non-irritating material, although excessive oral consumption may have a laxative effect. Dust may be irritating to the eyes and therefore eye protection is recommended.
Laxative effect may occur if consumed orally in large quantities.
Nontoxic and nonirritant, however, toxicity has been known to be with polyethylene glycols of low molecular, hence not macrogol 6000. Large quantities, when consumed orally, can produce a laxative effect. Eye protection is recommended.
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Not absorbed systemically following oral ingestion and is therefore regarded as an essentially nontoxic material. Irritant if inhaled and prolonged excessive exposure may cause pneumoconiosis.
Polysorbates are commonly used for oral preparations and therefore are regarded as nontoxic and nonirritant substances, however, gloves and eye protection are still recommended. Advised that polysorbates should be stored in a closed container, which is protected from light in a cool, dry place.
Considered to be a nonirritant and nontoxic excipient, however, eye protection, gloves and a dust mask are still recommended, as it may be irritating to the respiratory tract.
Eudragit L30-D-55 (ARTG no. 3700)
Polymethacrylates are wide used in oral preparations and are considered to be nontoxic and nonirritant excipients. Should be handled in a well-ventilated area and prevention of dust formation should be cautioned.
Eye protection and a dust mask are recommended. Potentially a risk factor in developing a latex allergy.
Chemical Compatibilities and Incompatibilities:
Due to omeprazole's acid labile structure, it is not stable in an acidic environment. Therefore, it is incompatible with excipients that can decrease the pH, and increase the hydrogen ion concentration, of the formulation. A preservative, such as benzoic acid, is incompatible with omeprazole due to its ability to decrease the pH of the environment by increasing H+ concentration and that its optimum pH for antimicrobial activity is below 4.5 (Rowe et. al 2009). With the pH of the formulation required to be at approximately 8-9 for the stability of omeprazole, benzoic acid would be unsuitable due to poor activity, and hence why hydroxybenzoate preservatives are used instead.
The activity of hydroxybenzoates, such as methylparaben and propylparaben, is reasonably reduced by the presence of non-ionic surfactants such as polysorbate 80 (which is used in the formation of the omeprazole pellets), as a result of micellisation. Hydroxybenzoates are also able to adsorb to other excipients, such as carboxymethylcellulose and methylcellulose or plastics, decreasing their activity. Other incompatibilities with hydroxybenzoates also include; atropine, iron, sorbitol, weak alkalis, and strong acids.
Sodium bicarbonate reacts with acids, acidic salts and alkaloidal to release carbon dioxide. Sodium bicarbonate is appropriate by acting as a buffer to maintain a suitable pH of approximately 9 to ensure activity of the hydroxybenzoate preservatives and desirable stability of omeprazole.
Impact on Design of the Product on its Intended Use:
For some patients, such as elderly people and children who cannot swallow intact tablets, an oral dispersion may be a useful alternative, assuming that the gastrointestinal tract is functioning well enough to absorb the medication (Ferron et. al 2003).
Optimum stability of omeprazole has been noted to be at a pH of 9, whereas at a pH of 1 or 2 causes rapid degradation of the omeprazole structure. This is the reason why solid dosage forms, such as tablets, are formulated with enteric coats, or capsules contain enteric-coated pellets, to avoid acid degradation in the stomach. However, this is method cannot be achieved in a liquid formulation due to the destruction of the enteric coating. Studies have found that omeprazole, when given as aqueous sodium bicarbonate suspensions through gastrostomy tubes, were 58-81% bioavailable compared with the tablet formulation and effective in raising intragastric pH (Ferron et. al 2003). Therefore, omeprazole dispersion formulations contain sodium bicarbonate solution to raise gastric pH, prevent acid attack on the omeprazole structure, and therefore increasing stability.
The product is intended to be used once daily for a period of time, and due to the product's high water content, it will require some preservative activity to prevent contamination and hence, increase shelf life. Compound Hydroxybenzoate Solution APF has been used in this formulation because it contains propylparaben and methylparaben. These benzoates are more active against yeasts and molds than against bacteria, however, they do have more activity against Gram-positive bacteria compared to Gram-negative bacteria. The activity of the benzoates is increased when used in combination to have additive effects, such as the use of both propylparaben and methylparaben. The activity of benzoates increases with increasing alkyl chain, consequently, the solubility decreases.
Acceptable Quality Control Tests:
A large determinant of omeprazole's stability is due to the pH of the suspension. Therefore, it would be recommended that testing the pH of the formulation after a period of time could possibly detect the extent at which omeprazole has degraded, such that if the pH was 4, there would be a high possibility that the concentration of omeprazole will not be 2 mg/mL. To confirm the extent of omeprazole degradation, mass spectrometry can be used, where more than 10% degradation is considered to no longer be an appropriate formulation.
HPLC can be used during the production process to identify any possible impurities and degradation products and their concentrations.
Using omeprazole in its pure form can help improve the formulation, possibly due to excipients in the solid dosage formulation can be incompatible with the solvents or preservatives that are used to produce the liquid dosage form. In this case, there is a known incompatibility with polysorbate 80 decreases the activity of the benzoate preservatives that are required in this APF formulation.