A Hard Pill to Swallow: How does the Size of Pharmaceutical Capsules affect the Rate of Reaction

Why?

The world becomes evermore reliant on prescription drugs each day. Innovation in the pharmaceutical world is needed to meet the demands of this lifesaving industry. In the process of the scientific method often some factors affecting rate of reaction are overlooked. Many patients take two pills of the exact same dose instead of taking a single pill of a larger dose. Medication volume could affect this but could capsule size affect the efficiency of the drugs? By understanding how the size of pharmaceutical capsules affects rates of reactions we could improve patient comfort, limit plastic waste in the industry and create more accurately targeted therapeutic responses. As someone, who could never swallow a pill as a young kid to later working in a pharmacy, seeing first hand the plastic waste of larger pill sizes it became apparent the need to understand capsules sizes' therapeutic impacts.

Approach:

Capsule sizes are universal from 000, the largest, to 5, the smallest. This means there are 8 main sizes of capsules on the market. Globally, 80% of the 620 billion pharmaceutical capsules produced are made from gelatin. Gelatin, being animal-based raises ethical concerns and Muslim community are left without inclusive options to their dietary preferences. Gelatin and Hydroxypropyl methylcellulose (HPMC) were used in sizes 000, 0 and 2.

Objectives:

Examine the differences in rates of reaction between HMPC and Gelatin Capsules ensuring more inclusive approaches to pharmaceuticals

Understand the differences in rates of reaction between the capsule sizes 000, 0 and 2

Experimental Design:

Testing Dissolution Design:

To understand the rate of reaction of capsules, the methodology was designed in alignment with guidance from the U.S. Department of Health and Human Services Food and Drug Administration Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug Products Containing High Solubility Drug Substances. By recreating the environment in the digestive system, using a pH of 1 with the use of 0.1M Hydrochloric Acid, using a magnetic stirrer to account for the movement in the stomach at 50 revolutions per minute and no surfactant, many of the criteria were followed. This environment was created in a 250 ml conical flask, which was connected to an inverted eudiometer  in a closed system which could measure the gas produced from a reaction.

Pharmacological Mechanism:

An Acid-Base reaction would create a visible and quantifiable reaction for the given Dissolution Testing Design. The earliest trials used Calcium Carbonate and Aluminum Carbonate, the two most common non-prescription Antacids but the reaction was not aggressive enough to force carbon dioxide gas into the eudiometer. Restricted from using prescription drugs in my Lab space, I decided to use Sodium Bicarbonate, a prescription antacid which is also a common household product. Once the earliest proof of concept trials were complete, I decided to fill all capsules with 300 mg of Sodium Bicarbonate Powder as this was the greatest volume which could easily fit into the size 2, small capsules and was similar to the common dosage of 325 mg on the market. These capsules were all filled in a retail pharmacy setting using pharmaceutical grade measurement instrumentation.

Research Question:

How does the size of pharmaceutical capsules affect the rate of reaction in acidic solutions of hydrochloric acid (HCl) to imitate stomach acid with Sodium Bicarbonate (NaHCO₃)?

Results:

Initial Hypothesis:

The largest capsules (Size 000) of both HPMC and Gelatin will dissolve faster than the medium size (Size 0) counterparts due to a higher surface area exposed to HCl solution. The smallest size (Size 2) will dissolve the slowest due to less surface area exposed to the HCl. Therefore the rate of reaction will be the greatest in the largest capsules and the lowest in the smallest capsules. Due to Gelatin’s high water solubility, it is likely that the rate of reaction will be greater in the Gelatin trials compared with the Hydroxypropyl methylcellulose as the capsule will dissolve quicker.

Qualitative Analysis:

The gelatin capsules got macroscopically larger, likely due to gelatin’s high water solubility. Despite the absorption of the aqueous solution the reaction did not occur until far later. After splitting the enlarged aqueous solution, filled halves would sometimes re-seal. This meant that the capsules would rupture but no reaction would occur until later. This was observed in Trial 2 and 3 in the size 000 gelatin and trial 2 and 4 in the size 0 gelatin trials.

The HPMC capsules did not get macroscopically larger. The divide of the two halves was clear and a more intense reaction was observed. The time from the rupture until the bubbles of CO₂ was faster causing greater pressure in the tubing likely giving a more precise value.

Quantitative Analysis:

The Quantitative results can be seen in Figure 1 for Gelatin and Figure 2 for HPMC. Standard Deviation was used to understand average deviation from the mean, due to time restrictions there are only 5 trials per size and capsule type. This means that the standard deviation is high. The unpredictability of the gelatin capsules rupture seen in the qualitative analysis could be responsible for these statistical values. A greater sample size would likely reduce Standard Deviation making the results more precise.

Conclusion:

This experiment concluded that capsule size does have an effect on rate of reaction. The size 2, of HPMC and gelatin, dissolve faster than their size 0 counterparts. The rate of reaction is 0.900 cm3min-1 in the size 2 HPMC which is greater than the rate of 0.721cm3min-1 of size 0. The size 0 to size 000 sees a similar pattern, the rate of reaction of size 000 is 0.441cm3min-1. The results of the gelatin are relatively proportional to the HPMC. The size 2 has a rate of reaction of 0.432cm3min-1, which is greater than size 0 at 0.376cm3min-1, which is greater than size 000 at 0.266 cm3min-1. The evidence contradicted the hypothesis. Through qualitative and quantitative analysis, HPMC rates of reaction are faster due to their structure and mechanism of release while smaller capsules also dissolve faster, this data could help guide industry application improving patient comfort, environmental standards, reducing packaging sizes and reduce the environmental impacts of gelatin products. Making pharmaceuticals more accessible, ethical, and conscientious improving individual and environmental wellness.

Improvements:

Efficiency could be improved by replacing the magnetic stirrer with an orbital shaker and using an industrial capsule filler.

Lab constraints prevented full FDA guidance's compliance. Extensions would likely incorporate a constant 37.5+-0.5℃ temperature and 500ml of HCl.

Additionally, testing various gelatin and HPMC brands is a vital extension, as material quality significantly impacts release rates.

These adjustments would enhance the experiment's efficiency, accuracy, and alignment with industry standards. Time was one of the largest constraints due to the equipment's low capacity.

Next Steps:

Working with a Post-Secondary Institution with a more robust research capacity

Thank you to Keir Campbell, Alex Wolf and the amazing teaching staff at Northumberland Regional High School for supporting my love and curiosity for learning.

Thank you to my Parents and all the Staff at Pharmacy First Ltd. for allowing me to use their scale and support my learning in the pharmacy world. They have taught me so much about the complexities of healthcare from pharmacology to global health and have inspired me to pursue a career in medicine.

Thank you to Eliza Abbass and Kim Frenette for their dedication to our Chignecto Regional Science Fair and their guidance on this journey to CWSF.

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