Extemporaneous Compounding of Amoxicillin Suspensions During National Shortage

Abstract

The primary objective of the study is to compound amoxicillin 400 mg per 5 mL oral suspension using 2 formulations. Amoxicillin 500 mg capsules were mixed in a vehicle of Ora-Plus and Ora-Sweet (1:1), as well as an Ora-Plus/Ora-Sweet vehicle alkalinized with sodium hydroxide 20% (w/v) solution to a pH of 6.

The suspensions were stored in PET plastic bottles under refrigeration and at room temperature for stability testing. The stability parameters examined were pH, concentration using high-performance liquid chromatography (HPLC), odor, suspendability, and appearance for 10 days. Suspensions of both vehicles were stable at room temperature and under refrigeration for 10 days.

Background

Amoxicillin is a broad-spectrum, penicillin-based antibiotic that binds to penicillin-binding-proteins (PBP) to inhibit cell wall synthesis.¹ Amoxicillin is commercially available as tablets, chewable tablets, capsules, and oral granules for suspension.

Amoxicillin is rapidly absorbed upon administration, distributes through most body tissues and fluids, and is primarily eliminated renally as an unchanged drug (60%). The FDA labeled indications of amoxicillin include treatment of pharyngitis, tonsilitis, otitis media, urinary tract infections, and Helicobacter pylori eradication.

As of November 2022, amoxicillin suspension has been on a national shortage list.² The FDA has permitted temporary compounding of amoxicillin suspensions. The compounding procedure must use commercially available dosage forms as the source of amoxicillin (i.e., tablets, capsules) and must require wetting by trituration to reduce dust. In addition, the FDA requires dedicated equipment for compounding beta-lactams.

This includes using separate mortars, pestles, personal protective equipment (PPE), and segregated areas of storage. Deactivating, cleaning, and disinfecting must be completed after compounding. The beyond-use date of the compounded preparation should not exceed that of the commercial product and the storage recommendation should not differ from the commercial product. 

Approach to Formulation

In accordance with the restrictions from the FDA, the proposed formula uses contents from amoxicillin 500 mg capsules mixed in a suspension vehicle. For this study, 2 vehicles were examined.

The first vehicle consists of Ora-Plus (Padagis) and Ora-Sweet (Padagis) in a 1:1 mixture. Ora-Plus consists of microcrystalline cellulose, xanthan gum, carrageenan, and carboxymethylcellulose sodium as suspending agents, citric acid and sodium phosphate as buffering components, simethicone as a defoaming agent, and methylparaben and potassium sorbate as preservatives in an aqueous base.³

Ora-Sweet consists of sucrose, berry flavor, citric acid, and sodium phosphate as buffers, methylparaben and potassium sorbate as preservatives, and small amounts of glycerin and sorbitol to prevent cap-lock.4 Ora-Plus has final pH between 4.0 to 4.5, whereas Ora-Sweet has a pH of 4.3.^3,4

According to the USP monograph for amoxicillin for oral suspension, the pH range is between 5 and 7.5.⁵ Therefore, the stability in an alkalinized vehicle of Ora-Plus and Ora-Sweet (1:1) with sodium hydroxide 20% (w/v) solution to yield a pH of 6 was examined.

The suspensions were stored in amber PET bottles in the refrigerator (2°C–8°C) and at room temperature (20°C–25°C) and then scheduled for assessment over 10 days. The stability parameters examined were pH, concentration using high-performance liquid chromatography (HPLC), suspendability, and appearance for 10 days.

The stability criteria were defined as retaining the labeled concentration +/- 10% measured by the HPLC method, inspecting the physical characteristics for changes in visual appearance, suspendability, and odor. The changes in visual appearance included color and precipitation during the in-use stability testing. The suspendability was evaluated by the homogeneity of suspensions after 5 shakes by hand.

The changes in odor were monitored for the presence of an unpleasant smell. The results were reported as change and no change. The pH measurement was obtained by direct immersion of the electrode in the compounded suspension and the pH reading uncertainty was ± 0.1.

Procedure

1. Measure equal quantities of Ora-Plus and Ora-Sweet syrups. Mix until homogeneous. For the alkalinized vehicle, add dropwise enough sodium hydroxide 20% (w/v) to yield a pH of 6. Prepare excess vehicle to ensure desired quantity can be prepared. The non-alkaline vehicle was used as is without any further pH adjustment.
2. Unlock and pour the contents of amoxicillin 500 mg capsules into a glass mortar. Triturate to reduce particle size.
3. Add a small amount of the prepared vehicle to the powder to wet. Triturate to form a uniform paste.
4. Geometrically add small amounts of the vehicle to the wetted mass until pourable.
5. Transfer the liquid to a calibrated amber bottle.
6. Rinse mortar and pestle with the vehicle until drug residue is adequately transferred to the calibrated amber bottle.
7. QS to final volume with the vehicle. Cap the bottle and shake well. Label and store for stability testing.

Components Used in the Study

The main formula contains amoxicillin capsules, Ora-Plus, Ora-Sweet. Amoxicillin 500 mg capsules by Aurobindo Pharma were used in the study.

According to the package insert, each capsule contains amoxicillin as the trihydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, and titanium dioxide in a gelatin capsule.¹ Ora-Plus and Ora-Sweet were previously described in the Approach to Formulations section.

Monobasic potassium phosphate, potassium hydroxide, acetonitrile, and the certified amoxicillin reference standard (RS) were purchased from Sigma-Aldrich; pH-meter was from Mettler-Toledo; 0.45 µm nylon filters, the HPLC vials were purchased from VWR; the ultra-pure water was obtained from Barnstead system purchased from Thermo Fisher; High-performance liquid chromatography (HPLC) column was purchased from Waters; and the HPLC system Prominence controlled by LabSolutions software version 5.57 was from Shimadzu. Calculations and statistical analysis were done using GraphPad Prism software, version 9.4.1, 2-way ANOVA, where a p-value of less than 0.05 is a significant difference.

Assaying Amoxicillin⁵

As described in the United States Pharmacopeia (USP) official monograph for Amoxicillin for Oral Suspension (USP, 2022), briefly: 0.05 M potassium phosphate buffer adjusted with 8 M potassium hydroxide to a pH of 5.0. The isocratic mobile phase was a mixture of 4% of acetonitrile in the buffer.

• Standard solution: 1.2 mg/mL of amoxicillin RS in buffer.
• Sample solution: A measured volume of the compounded amoxicillin suspension was diluted quantitatively and stepwise in the buffer to obtain a nominal concentration of 1 mg/mL of anhydrous amoxicillin.

Then a portion of this solution was passed through a 0.45µm nylon filter. The HPLC system pumped the mobile phase at a 1.5 mL/minute flow rate. The solutions were injected into an octadecylsilane column coupled with an ultraviolet detector at 230 nm. The system suitability for the tailing factor requirements: not more than (NMT) 2.5, relative standard deviation (RSD): NMT 2.0%.

Observations and Results

The stability data points were collected and reported once a day as per the following days’ schedule: day 0–day 3 and day 6–day 10. For the assay, the HPLC system was suitable and met the standard system suitability, the tailing factor was 1.1, and RSD 1.0%. Furthermore, the theoretical plates were more than 6000, and both solutions standards and samples showed a consistent retention time of about 3.27 minutes (Figure 1). The results were calculated by LabSolutions software.

The results for both preparations pH 6 and pH 4.4 at 2 storage temperatures, were comparable and with no significant difference (p > 0.4), in terms of the assay and pH. Regarding the physical characteristics, there were no changes, as shown in Tables 1 and 2.

Furthermore, the variation in the assay results could be explained due to the content uniformity of the amoxicillin distributed in the sample taken from the compounded oral suspension (Figure 2).

Conclusion and Recommendation

Based on our findings, amoxicillin suspension can be conveniently compounded using commercially available amoxicillin capsules, Ora-Plus, and Ora-Sweet without affecting physical or chemical stability. Although this serves as a convenient recipe, there are certain points to consider when compounding the suspension.

Per the FDA guidance, dedicated or disposable equipment must be used. Therefore, separate mortars and pestles must be used if compounding with beta-lactams.

Another acceptable option is by using an electronic mortar and pestle, such as Unguator.⁶ These devices have the advantage of reducing particle size while incorporating the drug into the suspension media in a disposable container and disposable mixing blades. This approach reduces the time for cleaning glassware during the compounding process.

Further research is needed to verify the pH effect on the amoxicillin degradation in the compounded amoxicillin oral suspension taking into consideration: 1) changing the pH of the Ora-Plus and Ora-Sweet syrups from 4.4 to 6, and 2) the effect of pH 4.4 on amoxicillin stability. Of note, the pH limit of the official USP Amoxicillin and Clavulanate Potassium for Oral Suspension⁷ is 3.8–6.6, which makes the argument that the pH effect in the pH range of pH 4-6 might be minimum.

While this formulation does have flavoring through the Ora-Sweet component, some patients may wish to include additional flavorings to the formulation. According to the new USP <795> guidelines set to be official on November 1, 2023, the addition of flavorings fall under compounding standards.⁸

Due to the variability of the ingredients in flavoring components, the stability of this preparation with additional flavorings cannot be guaranteed. If a patient wishes to flavor it, the volume intended to deliver the dose can be mixed with sugar, chocolate syrup, or dessert topping and consumed immediately.⁹

It is important to note that this study examined stability for 10 days. The commercially available dosage form has a 14-day stability.¹⁰ If therapy needs to exceed 10 days, another batch must be prepared to fulfill therapy. In addition to labeling with the beyond-use-date, include a “shake well before use,” appropriate storage conditions, and any other requirements per state boards of pharmacy.

References

1. Amoxicillin. Package insert. Aurobindo Pharma Limited; 2018.
2. Center for Drug Evaluation and Research. Compounding Certain Beta-Lactam Products in Shortage Under Section 503A of the Federal Food Drug and Cosmetic Act. U.S. Food and Drug Administration. Published November 18, 2022. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/compounding-certain-beta-lactam-products-shortage-under-section-503a-federal-food-drug-and-cosmetic Accessed: December 5, 2022
3. Ora-Plus product information: Perrigo Inc.; 2019.
4. Ora-Sweet product information: Perrigo Inc.; 2019.
5. United States Pharmacopeia (2022). USP Monographs, Amoxicillin for Oral Suspension. USP-NF. Rockville, MD: United States Pharmacopeia. DOI: https://doi.org/10.31003/USPNF_M4140_01_01. Doc ID: GUID-6A431AD5-8C4D-4C1C-96B0-0E494534E7E2_1_en-US
6. Gako Deutschland GmbH. Gako Unguator https://www.unguator.com/ Accessed: January 17, 2023
7. United States Pharmacopeia (2023). USP Monographs, Amoxicillin and Clavulanate Potassium for Oral Suspension. USP-NF. Rockville, MD: United States Pharmacopeia . DOI: https://doi.org/10.31003/USPNF_M4190_01_01 .Doc ID: GUID-BF9F3A49-653F-45B1-A085-9FF00E84FC04_1_en-US
8. United States Pharmacopeia. USP <795> FAQs. https://go.usp.org/USP_GC_795_FAQs Accessed: January 17, 2023
9. Illinois Department of Public Health. Creating Amoxicillin for Infants and Children Exposed to a Disease. February 2020 https://dph.illinois.gov/content/dam/soi/en/web/idph/files/amox-final-feb2020-asmay2020.pdf Accessed: January 17, 2023
10. Amoxil powder for oral suspension. Package insert. Teva Pharmaceuticals; 2018