A Critical Assessment of Extemporaneous Formulations for Proton Pump Inhibitors: The Importance of Proper Vehicle Selection

Abstract

OBJECTIVE

To examine the influence of vehicles on the stability of extemporaneous suspensions of proton pump inhibitors (PPIs), to single out the formulation most suitable for children, providing appropriate evidence and arguments.

METHODS

A review was performed of data identified from Medline, Embase, Science Direct, as well as public digital archive PubMed, including reference texts, related to the field of stability testing of extemporaneous PPI suspensions.

RESULTS

Fourteen selected formulations of extemporaneous suspensions are presented and discussed. Depending on the vehicle and its composition, which was analyzed and explained in detail, the suspensions had various beyond-use dates (BUDs).

CONCLUSIONS

Selected vehicles and the process of preparation had great influence on the stability of extemporaneous PPI suspensions. The suspension with the longest BUD has been singled out, which is especially suitable for use in newborns. Because an explanation is provided for the influence of individual vehicle components on the stability of the mentioned suspensions, this can aid not only in the selection of an adequate formulation, but also in the development of new ones, which will be suited to individual patients.

Introduction

Proton pump inhibitors (PPIs) were introduced into clinical use more than 30 years ago. Ever since omeprazole was first used in 1988, PPIs have been widely used because of their effectiveness in the treatment of various gastric acid-related diseases. By their molecular structure, PPIs are substituted benzimidazoles. The mechanism of action of PPIs is based on the inhibition of gastric acid secretion, which is achieved by blocking H⁺, K⁺-ATPase, better known as a proton pump.¹ Six PPIs have been approved for use by the US Food and Drug Administration. These include omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole, and rabeprazole. This class of drugs represents the first choice in the treatment of esophagitis, non-erosive reflux disease, peptic ulcer disease, prevention of ulcers associated with nonsteroidal anti-inflammatory drugs, Zollinger-Ellison syndrome, and functional dyspepsia.² PPIs are also used in the eradication therapy of Helicobacter pylori.²

PPIs are often used for pediatric patients with enteral feeding tubes, ^3–5 even though registered pediatric liquid formulations are lacking.⁶ The available orally administered PPIs, like most oral dosage forms, are primarily found as solid formulations, such as tablets and capsules. These dosage forms have advantages over liquid formulations, including the convenience of carrying and taking them, easy identification, mostly neutral taste, but also greater microbiologic and chemical stability than liquid oral formulations.⁷

On the other hand, conventional solid dosage forms are not suitable for use in younger pediatric patients because they are designed to be swallowed whole. Pediatric patients, especially infants and children younger than 6 to 7 years, are usually unable to swallow solid oral dosage forms, and also need a dose adjustment. Therefore, the dosage form of choice in this population is a liquid preparation. However, suitable liquid preparations are often not commercially available, owing to several factors, one of which is a small market. Thus, community- and hospital-based pharmacists very often face the challenge of making extemporaneous liquid preparations to facilitate application and to provide an adequate dose to their pediatric patients. It has been reported that such liquid preparations account for about 40% of all preparations administered to pediatric patients.⁸

Compounding Challenges

Compounding involves combining, mixing, or altering the ingredients to create a medication tailored to the needs of an individual patient.⁹ If a pure active pharmaceutical ingredient (API) is available, it should be used to make extemporaneous preparations.¹⁰ Because pure APIs are not usually available in pharmacies, extemporaneous preparations are usually made from commercially available solid dosage forms, by simply pulverizing the tablets or removing capsule contents and adding either water or one of the commercially available vehicles. If the API or one of the excipients used in the formulation of tablets or capsules is insoluble, a suspension is formed.¹¹ Extemporaneous suspensions prepared in this way are very complex, bearing in mind the excipients added to the formulation, which aim to improve the stability of the preparation and the compliance of patients.¹¹

Commercially available solid dosage forms have documented stability studies with defined expiration dating. However, knowledge acquired from these studies cannot simply be transferred to devise liquid extemporaneous preparations made from the solid dosage forms. Keeping in mind the method of preparation, special attention should be paid to determining the chemical, physical, and microbiologic stability of the extemporaneous suspensions. An additional challenge in formulating stable PPI suspensions is the fact that these compounds are sensitive to low pH values.

Given the risks related to the preparation and use of extemporaneous preparations, it is recommended to set a strict shelf life for these preparations. The shelf life of extemporaneous preparations is defined in General Chapter <795> of the United States Pharmacopeia⁹ as a beyond-use date (BUD). The BUD is the number of days after which a compounded product may not be used and is calculated from the day of compounding. The maximum BUD for non-preserved aqueous dosage forms is 14 days in the refrigerator. Aqueous preparations are defined as those whose water activity is greater than 0.6. Water activity is the percentage of water that is freely available within the substance and is not chemically bound to other ingredients. This water can promote microbial growth or, through hydrolysis, degrade the API. Therefore, refrigeration is of utmost importance in reducing microbial growth in non-preserved preparations. Preserved aqueous preparations can be stored for up to 35 days at controlled room temperature (CRT) or in the refrigerator. On the other hand, in General Chapter <795>, nonaqueous formulations are divided into solid dosage forms with assigned BUD of 180 days in CRT or in the refrigerator, and other nonaqueous formulations such as suppositories, ointments, fixed oils, or waxes, with a BUD of 90 days at controlled CRT or in the refrigerator.⁹

Methods

A review was performed of data identified from Medline, Embase, Science Direct, as well as public digital archive PubMed, including reference texts, related to the field of stability testing of extemporaneous PPI suspensions. Reference texts^12–25 were included in which stability studies were performed by using stability-indicating methods and in which the suspension was considered stable if it retained more than 90% of the initial content. The results of the mentioned studies for 14 formulations are briefly presented, and the influence of vehicle components on stability of each suspension is discussed in detail.

Results

Our literature search identified 14 extemporaneous PPI formulations with stability-containing methods. These formulations are outlined in the Table. The specifics regarding each formulation are addressed in detail in the Discussion section.

Table.

Composition of the 14 PPI Extemporaneous Suspensions Reviewed

Formulation	PPI	Final Concentration, mg/mL	Source of PPI	Excipients Added	BUD
F112	Omeprazole	2	Capsules filled with pellets	Glycerin Croscarmellose sodium Simple syrup Methylparaben Propylparaben Purified water	Less than 24 hr
F212	Omeprazole	2	Capsules filled with pellets	Sodium bicarbonate (8%) Methylparaben (0.08%) Propylparaben (0.02%) Propylene glycol (1%) Purified water	30 days (refrigerated)
F312	Omeprazole	2	Capsules filled with pellets	Sodium bicarbonate (8%) Methylparaben (0.08%) Propylparaben (0.02%) Propylene glycol (1%) Xanthan gum Purified water	30 days (refrigerated)
F413,14	Omeprazole	2	Capsules filled with pellets	Sodium bicarbonate (8.4%) Purified water	14 days13,14 (CRT) 3013 or 4514 days (refrigerated)
F515	Omeprazole	2	Omeprazole pure powder	Sodium bicarbonate (8.4%) Purified water	45 days (refrigerated)
F616	Omeprazole	2	Omeprazole pure powder	SyrSpend SF Alka dry	92 days (refrigerated)
F717	Omeprazole	5	Omeprazole pure powder	SyrSpend SF Alka dry	30 days (CRT) 90 days (refrigerated)
F818,19	Omeprazole	2	Omeprazole powder for oral suspension	Purified water	7 days18 (CRT) 2818 or 4519 days (refrigerated)
F920	Lansoprazole	3	Tablets	Ora-Blend	3 days (refrigerated)
F1021	Lansoprazole	3	Capsules filled with pellets	Sodium bicarbonate (8.4%) Ora-Blend	90 days (CRT or refrigerated)
F1114,22	Lansoprazole	3	Capsules filled with pellets	Sodium bicarbonate (8.4%) Purified water	814 or 4822 hr (CRT) 722 or 1414 days (refrigerated)
F1223	Lansoprazole	3	Capsules filled with pellets	Sodium bicarbonate (8.4%) Ora-Sweet Ora-Plus	91 days (CRT or refrigerated)
F1324	Pantoprazole	2	Tablets	Sodium bicarbonate (8.4%) Sterile water for irrigation	62 days (refrigerated)
F1425	Pantoprazole	2	Tablets	Sodium bicarbonate (8.4%) Purified water	14 days (CRT) 90 days (refrigerated)

BUD, beyond-use date; CRT, controlled room temperature; PPI, proton pump inhibitor

Discussion

Numerous studies have been conducted to evaluate the stability of different formulations of extemporaneous suspensions of omeprazole.^12–19 This is not surprising, given that omeprazole is the most commonly prescribed PPI for pediatric patients who do not respond to commercially available doses.^3,17 Although omeprazole has low bioavailability (30%–40%) and a short half-life (0.5–1 hour), omeprazole is often the most affordable and cost-effective PPI.^1,2

The formulation F1 (see Table) represents an extreme case of such unstable suspension so that the general recommendations of United States Pharmacopeia cannot be applied to it, that is, the BUD is much shorter. This is not surprising, given that the formulation does not include any buffers to increase the pH value, which is necessary because omeprazole degradation occurs at a pH below 7.8.²⁶ With this in mind, it is imperative to develop a formulation with a pH around 8.

The formulation F2 (see Table) includes sodium bicarbonate, which maintains a higher pH value, thereby chemically stabilizing the preparation. Additionally, sodium bicarbonate is essentially nontoxic and a non-irritant material, easily available and affordable.²⁷

To ensure the microbiologic stability of formulation F2, 1% of compound hydroxybenzoate solution (Australian Pharmaceutical Formulary)²⁸ was used as a preservative. The solution consists of 8% methyl hydroxybenzoate (methylparaben) and 2% propyl hydroxybenzoate (propylparaben) in propylene glycol.¹² The final concentration of these substances in formulation F2 is 0.08% of methylparaben, 0.02% of methylparaben, and 0.9% of propylene glycol.

The use of parabens as preservatives is desirable, given the high pH of the formulation and the fact that parabens are effective in the pH range of 4 to 8.^27,29 A significant problem with the use of parabens is their solubility in water, which is 0.25% for methylparaben and 0.04% for propylparaben. The effective concentration of methylparaben is within the range of 0.05% to 0.25%, while for propylparaben it is 0.02% to 0.04%.^27,29 To find a compromise between solubility and efficiency, a combination of parabens can be used. Parabens used in combination exhibit a synergistic effect.²⁹ In this way, it is possible to use amounts at the lower end of the range of their effective concentrations, with an equally good preservative effect.

On the other hand, owing to the low concentration in formulation F2, it is obvious that propylene glycol does not act as a preservative because the range of its effective concentrations is 10% to 30%.^27,29 Thus, in F2 propylene glycol serves as a co-solvent.

The stability study has proven that the BUD of formulation F2 is 30 days in the refrigerator. This represents a significant improvement over the previous formulation. However, because preservatives and propylene glycol can cause serious side effects in newborns and children,^7,10 formulation F2 will be limited to use in adults only.

Formulation F3 has all the excipients of formulation F2 with the addition of xanthan gum. Xanthan gum is very suitable for preparations for children because it is nontoxic. On the other hand, xanthan gum is compatible with most other pharmaceutical ingredients and has good stability and viscosity properties in a wide pH range (pH 3–12),^27,30 which is very significant given the high pH of the considered formulation. The main reason for the addition of xanthan gum to formulation F3 is to increase viscosity.¹² Xanthan gum has viscoelastic properties and can modify the rheologic properties of liquid preparations by increasing their viscosity. This can ensure the physical stability of the suspension by slowing down precipitation. However, xanthan gum also acts as a stabilizing and suspending agent^27,30 because it leads to controlled flocculation in suspensions,³¹ creating loose precipitates and allowing redispersion of suspensions while preventing cake formation. This also improves the physical stability of the suspension.

Because formulation F3 has the same BUD as formulation F2 (30 days in the refrigerator), it is obvious that the addition of xanthan gum to the formulation did not lead to improved stability.

In formulation F4, only an appropriate pH value is provided, given the presence of sodium bicarbonate, which increases the pH value. This formulation is known as simplified omeprazole suspension. Because no preservatives were added, the preparation could not be protected microbiologically. However, BUD was determined by a decrease in omeprazole content below 90% of the baseline.¹³

As can be seen from the presented results, 3 formulations of omeprazole (F2, F3, and F4) had a BUD of 30 days (in the refrigerator).^12–14 All 3 formulations were made from a solid oral dosage form, namely pellets. Of these formulations, formulation F4 had the simplest composition, except for the presence of API, a 2-component vehicle (sodium bicarbonate and water)—which is why formulation F4 would have an advantage over the previous one.

The advantage of formulation F4 is supported by the results of a study conducted by DiGiacinto et al,¹⁴ proving a BUD of 45 days in the refrigerator. In this case, BUD is extended by packaging material. While Quercia et al¹³ stored their samples in clear glass vials, DiGiacinto et al¹⁴ used amber-colored plastic syringes. With this in mind, it is recommended that simplified omeprazole suspension be stored in amber containers.

Formulation F5 also contained omeprazole suspended in 8.4% sodium bicarbonate solution but was prepared with omeprazole powder (pure substance). Because this formulation was also stored in amber containers, its BUD was the same as that of formulation F4 (45 days refrigerated).

Formulation F6 showed the longest BUD. This suspension was also made from omeprazole raw substance with the addition of commercially available vehicle SyrSpend SF Alka dry (Fagron [formerly Gallipot], St. Paul, MN). SyrSpend SF Alka dry consists of only 3 substances: modified starch, calcium carbonate, and sucralose. Modified starch acts as a suspending agent. Calcium carbonate provides a pH greater than 8, which is imperative for the omeprazole formulations as stated previously. Sucralose, an artificial sweetener, masks the unpleasant taste of the API. This provides an advantage over the simplified formulations containing sodium bicarbonate, which can further intensify the unpleasant, bitter taste of omeprazole. The use of sweetener is important because it improves the palatability of the preparation, and thus acceptability by the children, thereby increasing patient adherence.^7,16,17

Formulation F7 was prepared in the same way as F6, with a difference in the concentration of the API.¹⁷ Therefore, the BUD is almost identical to that of F6.

Omeprazole powder for oral suspension was used to prepare formulation F8. In addition to the API, this powder contains sodium bicarbonate, xylitol, sucrose, sucralose, xanthan gum, and flavorings.³² The necessity of sodium bicarbonate and the role of xanthan gum was discussed above for previous formulations. For taste-masking, a combination of xylitol, sucrose, and sucralose is used. Xylitol gives an additional cooling sensation, making the taste more pleasant.²⁷ The conducted stability studies established 2 different BUDs (28 days¹⁸ and 45 days¹⁹). The reason for this difference is study duration. Burnett and Balkin¹⁸ conducted their study for 28 days, and at that time point, omeprazole content was almost unchanged in comparison to the beginning of the study. On the other hand, the study of Johnson et al¹⁹ lasted for 45 days, during which omeprazole content remained within the limits.

Formulation F9 contains lansoprazole as the API, dispersed in Ora-Blend (Paddock Laboratories, Minneapolis, MN), a commercial vehicle. Ora-Blend is characterized by a pH value of about 4.3,³³ which is slightly acidic media, and as such, has a negative effect on the stability of lansoprazole. Because there is no buffer in the formulation to bring pH to optimum, it is not surprising that the BUD of this formulation is only 3 days in the refrigerator.

How significantly the appropriate pH of the formulation affects the stability of the extemporaneous suspension can best be seen by comparing the composition and BUD of formulation F9 and F10. Sodium bicarbonate was included in the F10 formulation, which automatically resulted in the extension of the BUD to 90 days in the refrigerator and CRT. It is important to note that the excipients or manufacturing process used to make lansoprazole pellets may have an additional positive effect on suspension stability because F9 is made from orodispersible tablets.

Formulation F12 has a similar composition, which in addition to sodium bicarbonate, contains a mixture of Ora-Sweet( Paddock Laboratories, Minneapolis, MN) and Ora-Plus (Paddock Laboratories, Minneapolis, MN) commercial vehicles. A mixture of these 2 vehicles in a 1:1 ratio results in an Ora-Blend vehicle. Because Ora-Sweet has a pH of 4.3 and Ora-Plus a pH between 4.0 and 4.5,^34,35 their mixture will have a pH value close to that of Ora-Blend. Therefore, it was necessary to add an alkalizing agent to the formulation. This formulation also has BUD of 91 days at CRT or in the refrigerator.

Ora-Blend and a mixture of equal ratios of Ora-Sweet and Ora-Plus have a complex composition. They contain sucrose, glycerin, and sorbitol as sweetening agents, as well as flavorings, which makes them acceptable to patients in terms of taste and smell. Glycerin can also act as a wetting agent for insoluble powdered substances. Microcrystalline cellulose and sodium carboxymethyl cellulose act as viscosity-increasing agents. Xanthan gum and carrageenan play the role of suspending agents.²⁷ Calcium sulfate acts as a thickening agent but could also provide smoother-taste suspensions.³⁶ They also contain citric acid and sodium phosphate as buffers, simethicone as an antifoaming agent, and methylparaben and potassium sorbate as preservatives.^33–35

The stability data for formulation F11, also known as simplified lansoprazole suspension, are contradictory. While DiGiacinto et al¹⁴ found this formulation to be stable for 8 hours (CRT) and 14 days (refrigerated), Morisson et al²² reported the BUD as 48 hours (CRT) and 7 days (refrigerated). This could be due to the different composition of lansoprazole pellets or different grades of purity of excipients in suspension, used in the abovementioned studies. Because the authors did not provide the name (brand or generic) of the drug product, this assumption could not be proved.

The other issue with F11 is its impaired stability compared with that of F4, which has the same excipients. If an optimal pH is provided, the answer to the question of impaired stability may be found by analyzing the characteristics of the API. Lansoprazole is rapidly degraded in aqueous solutions. The half-life at CRT is 30 minutes at pH 5, and about 8 hours at pH 7.³⁷ This means that Morrison et al²² achieved a certain stabilization in the formulation, because BUD is prolonged for 30 hours.

On the other hand, F11 illustrates how important the choice of vehicle is for the stability of the formulation, in addition to achieving an adequate pH value. Unlike the formulations F10 and F12, which have been prepared with commercial vehicles and have a BUD of 90 days, F11 has a BUD of 8 (or 48) hours. Obviously, the viscosity-increasing agents, suspending agents, and preservatives play a role in preventing the degradation of the API, as BUD was determined on the basis of decrease in its content, and the preparation was physically and microbiologically stable.

The composition of the 2 formulations of pantoprazole F13 and F14 is similar. They differ only in the type of water used in their preparation. While F13 was prepared with sterile water for irrigation, F14 was prepared with purified water. However, BUD for formulation F13 is 30 days less than BUD for F14. The reason is probably that formulation F13 was stored in amber polyethylene terephthalate bottles,²⁴ while F14 was stored in an amber medical glass bottle.²⁵

Conclusion

The preparation of a stable PPI suspension is achieved by selecting the appropriate compounding process as well as by selecting the appropriate vehicle. Suspensions made from pure raw substances showed greater stability than those made from oral solid dosage forms. In addition, the absolute imperative from the aspect of PPI stability is the pH of the formulation above 8. Both suspensions (F1 and F9) with inadequate formulation pH proved to be extremely unstable.

The vehicle used also had a significant effect on improving the stability of the preparation. Commercial vehicles are particularly suitable because they reduce the number of steps in preparing the suspension, thereby reducing possible errors. Additionally, they contain flavoring agents, which are important because they improve compliance of young patients. These vehicles allow the preparation of elegant suspensions acceptable to the patient. However, it is important to note that commercial vehicles have inadequate pH, and therefore the addition of sodium bicarbonate as an alkalizing agent is necessary with PPI formulations. This combination of excipients results in PPI suspensions that remain stable for 90 days.

Of all presented extemporaneous PPI suspensions, formulations F6 and F7 stand out—we recommend using either of these formulations for omeprazole. They are composed of the API and SyrSpend SF Alka dry vehicle, only. Because SyrSpend SF Alka dry vehicle contains modified starch acting as a suspending agent, calcium carbonate that provides a pH above 8, and sucralose, F6 and F7 did not require the addition of sodium bicarbonate to achieve optimal pH. Furthermore, the advantage is the presence of sucralose, which as a sweetener improves the taste and thus acceptability of the preparation, so no additional sweetener was required in these formulations. Another advantage of this vehicle is the absence of sorbitol, ethanol, as well as propylene glycol, and other preservatives, and it is therefore this vehicle or one with similar composition and properties that can be very suitable for use in newborns. If lansoprazole or pantoprazole are preferred over omeprazole, we recommend F10 and F12 or F14, respectively. These formulations showed the longest BUD as compared with others with the same APIs and had acceptable composition.

ABBREVIATIONS

API

active pharmaceutical ingredient

BUD

beyond-use date

CRT

controlled room temperature

PPIs

proton pump inhibitors

Funding Statement

Disclosures. The authors declare no financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria.