Project Final Report

ENGR 103 - Spring 2017
Freshman Engineering Design Lab

“Manipulating Drug Release Rates Utilizing Alginate-Based Hydrogel”

Final Report

Date Submitted: May 26, 2017

Submitted to:	Dr. Hao Cheng, technical advisor, hao,cheng@drexel.edu Mohammad Nozari, mn468@drexel.edu
Group Members:	Brooke Barney, bab384@drexel.edu
	Oluwadamilola Bolarin, odb23@drexel.edu
	Samuel Estrin, see54@drexel.edu
	Vriti Khurana, vk372@drexel.edu
	Elizabeth Moroz, eam422@drexel.edu

Abstract:

“Alginate is a naturally occurring polymer that is finding increasing applications in the biotechnology industry[1].” The purpose of this project is to investigate the properties of alginate-based hydrogels and integrate the hydrogels into a drug delivery system. Specifically, the project focuses on manipulating the ratio of volume to surface area of  the hydrogels to prolong drug delivery. Since many current drugs are hydrophobic, the drug used was Vitamin D3, which is a fat soluble vitamin that many people take as a daily dietary supplement. Along with analyzing spectroscopic data collected from the experiments, the main deliverables of the project are 3D molds used to cast the hydrogels into various shapes; the hydrogel itself, that is designed for prolonged drug delivery within the human body; and a blog that documents all technical activities and progress. Over the course of ten weeks, the team investigated the properties of hydrogels, designed 3D molds , conducted testing to determine dissolution rates, and recorded weekly challenges in the blog.

Figure 1: Chemical Structure of Sodium Alginate [2]

Introduction

1. Problem Overview

This project was selected from a plethora of issues revolving around the implementation of hydrogels. Modern medicine requires the produced drugs to not only contain appropriate amounts per dose, but, to release these drugs to the system at specific rates. Additionally, researchers must overcome the hydrophobic nature of many drugs .Utilizing the alginate polymer, the group investigated the release rates of the implemented drug, Vitamin D3, by manipulating the surface area to fixed volume ratio of the formed hydrogel. However, this project had constraints the group had to adhere to such as the size and mass of the hydrogel formed, ease of consumption for the end user and molecular weight of all compounds involved in the process.

2. Existing Solutions

Currently, the United States Food and Drug administration has established thorough regulations and production constraints on oral medicines. Laws such as the FDA guidelines [4] on shape, size and other physical properties on tablets and capsules ensure good quality of medicine. However, advances in hydrogel-based drug administration have made some of these regulations not only incomprehensive and inextensive, but, a hinderance to medical advancements.

3. Project Objectives

Through the manipulation of surface area to fixed volume, the group set out to investigate drug release rates in an endeavour to improve drug implementation outside outdated FDA regulations. Efficient regulations, such as the tablet and capsule size [4] were adhered to. By attaining sufficient knowledge of hydrogel and Vitamin D3 properties, the group successfully mass-produced hydrogels of proportionally ranging surface area to fixed volume ratio by 3D printing flexible molds. This ensured that all other factors such as drug concentration and alginate polymer mass could be controlled between individual hydrogels. From an idealistic point of view, the group explored different release times of Vitamin D3, a drug needed in relatively small amounts in a specific time frame, to find a mechanism that releases the drug at an appropriate rate per dose.

2. Technical Activities

1. Formation of Alginate Hydrogels

The initial investigative task required for the project is to develop a hydrogel procedure that is specific to the brand of alginate that was acquired. The procedure focused on the main components of our hydrogel, alginate, calcium chloride, and Vitamin D. First, the formation of alginate gels underwent a very vigorous trial and error process until it was finally perfected. The team discovered that to acquire the desired viscosity of the alginate, the amount of water must be proportional the amount of alginate powder. Second, after it was decided to use a 2.0 M CaCl2, the team chose to create a large stock solution to avoid contamination or experimental variations. The solution was used consistently throughout the course of the term. The third task involved the formation of the hydrogels in the mold. The procedure started with rinsing the inside of the mold in a calcium chloride bath. The alginate infused with vitamin D was then put into the mold and filled to the top rim of the mold itself. A final calcium chloride layer was added to the side of the hydrogel that was exposed in the mold. This final step created the hydrogel and ensured that the hydrogel itself did not leak.

2. Molds for Alginate Hydrogels
1. Volume and Surface Area Calculations

The task of choosing cylindrical molds dimensions was determined by taking a Calculus based approach. The formulas for calculating the volume and surface area of a cylinder were used to calculate dimensions of cylinder with a constant volume and variable surface areas. It can be seen from the table and a sample calculation are shown below that there are two possible radius and height dimensions for each surface area with the exception of the minimum surface area.

By manipulating to volume equation to solve for the height, it was possible eliminate a variable in the formula for surface area. After algebraically simplifying the surface area equation, the derivative of was found and used to determine the minimum radius and surface area of a cylinder with a volume of 750 mm3. Graphically the solution can be see below.

Figure 2: Matlab graphical display of surface area formula

Table 1: Summary of cylindrical mold dimensions

Volume (mm3)	Surface Area (mm2)	Radius (mm)	Height (mm)	Ratio of Surface Area to Volume
750	456.97	4.9237	9.8476	0.609293333
750	580	2.8323	29.759	0.773333333
750	650	2.4498	39.7786	0.866666667

Table 2: Summary of cylindrical mold dimensions

Volume (mm^3)	Surface Area (mm^2)	Radius (mm)	Height (mm)	Ratio of Surface Area to Volume
750	456.97	4.9237	9.8476	0.609293333
750	580	7.8732	3.8513	0.773333333
750	650	8.7224	3.1379	0.866666667

2.2.2    Mold Designs

The creation of 3D printed molds is the most feasible option given the project’s time constraint of ten weeks and the goal to minimize the overall cost of the project. Additionally, utilizing plastic molds increases precision and decreases variability during experiential testing.

Throughout the project, the team explored several different mold designs created through the use of PTC Creo. First, the team designed molds with non-uniform cross sectional areas, such as square-based pyramids, spheres, and cones all of volume 250 mm3, to test release rates of hydrogels. After initial experiments, the group adjusted to volume to 750 mm3 and designed hydrogels using uniform cross sectional area cylinders. Six cylinders of fixed volume 750 mm3 were formed by manipulating the radius to cross-sectional length. Further testing showed that cylinders, where its cross sectional length was far greater than its radius, proposed challenges in  hydrogel formation. The final mold dimension used are displayed in Table[1] and were printed using TPU(Thermoplastic Polyurethane) filament.

3. Project Timeline

Table 3: Hydrogel Creation Gantt Chart

	Week
Task	1	2	3	4	5	6	7	8	9	10
Investigation, Research, Proposal	X	X	X
Order Materials/Wait For Arrival		X	X	X
Alginate Hydrogel Formation				X	X	X
Hydrogel Experimentation: Shapes, Dissolution Rates				X	X	X	X	X	X
Use Data From Experimentation to Finalize Hydrogel						X	X	X	X
Create Final Report and Presentation								X	X	X

 

2.4 Project Budget

Materials to be used in this project are shown in the table below.

Table 4: Design Budget

	Category	Projected Cost
1	Sodium Alginate Polymer	$20 for 16 oz
2	Calcium Chloride	$12.94 for 16 oz
3	Vitamin D3	*
4	100 Pipettes	*
5	Gloves	*
6	Glassware/Test tubes	*
	TOTAL	$32.94

* Denotes a material that is owned, borrowed, shared or created without cost.

3. Results

1. Final Deliverables

As stated in the initial project proposal, the final deliverables include:  successful creation of alginate based hydrogels using molds, the creation of the molds themselves, the CAD models of the molds, and a blog. The blog proved to be an organizational resource and an accurate record of the challenges encountered at each step of the project. Throughout all of the challenges, the team’s objectives and final deliverables were accomplished.

The first main challenge began with 3D printing the molds. Since the molds were printed using TPU, printer settings had to be determined that resulted in a successful and accurate print. Additionally, the initial molds were too small to remove the gels from and needed to be enlarged. The team also needed to determine the composition ratios of alginate and calcium chloride in order to create a gel that would hold shape after being removed from the molds. After making necessary adjustments, the creation of the hydrogels, molds, and CAD models was accomplished.

2. Spectroscopy Test and Data

Figure 3: Spectroscopy results for a radius: 4.9237 mm  and height: 9.8476 mm

Figure 4: Spectroscopy results for a radius: 7.8732 mm and height: 3.8513 mm

Figure 5: Spectroscopy results for a radius: 8.7224 mm and height: 3.1379 mm

4. Discussion

1. Spectroscopy Data Analysis

Data will be analyzed after a technical decision is made. Due to the low solubility of Vitamin D3, it will be challenging to determine the concentration of Vitamin D3 released based on the spectroscopy data that was collected for each cylindrical shape.

2. Sources of Error

Sources of error could have occurred while conducting experimental procedures. These errors are, but not limited to, forming the hydrogel in the mold, removing the hydrogel from the mold and acquiring samples from the solutions accurately.

4.3 Project Improvements and Reflection

Possible improvements to the project include conducting more technical research prior to experimentation. Additionally, the team should make themselves aware early on what is not fully understood and seek out the answers from the faculty advisor.  

5. References

1. Gombotz, Wayne R., and Siow Fong Wee. "Protein Release From Alginate Matrices." Advanced Drug Delivery Reviews 64 (2012): 194-205. Web. 10 Apr. 2017.
2. “Molecule Structure.” World of Chemicals, World of Chemicals, 2017, www.worldofchemicals.com/chemicals/chemical-properties/sodium-alginate.htmlAccessed 3 May 2017.
3. Zhang, Shiyi, Andrew M. Bellinger, Dean L. Glettig, Ross Barman, Young-Ah Lucy Lee, Jiahua Zhu, Cody Cleveland, Veronica A. Montgomery, Li Gu, Landon D. Nash, Duncan J. Maitland, Robert Langer, and Giovanni Traverso. "A PH-responsive Supramolecular Polymer Gel as an Enteric Elastomer for Use in Gastric Devices." Nature Materials 14.10 (2015): 1065-071. Web. 11 Apr. 2017.
4. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). “Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules: Guidance for Industry.” (June 2015). Web. 15 April 2017.