A novel method for measuring drug dissolution rates uses a quartz crystal microbalance system that can directly and rapidly measure mass changes, requiring a much smaller sample size than traditional methods. The quartz crystal oscillates at a resonant frequency that changes with applied mass. Data from dissolution tests using benzoic acid showed regions for recrystallized mass, unstable water contact, and solely mass dissolution. Automating the analysis through a computer program dynamically determines these regions to more precisely calculate dissolution rates compared to manual analysis. However, high-volume testing was found to introduce errors and limit the quartz crystal lifespan to about 50 tests.

1. A novel dissolution testing methodology has been
developed using a commercial quartz crystal
microbalance (QCM) system to measure dissolution
rates of drugs. Our technique is more advantageous
than current pharmaceutical methods, which are
resource, sample, and time intensive. Current methods
measure dissolution rate by taking samples of the
solution at given time intervals and determining the
concentration until the drug has fully dissolved.
However, the QCM method is capable of measuring
mass changes directly and rapidly. Additionally, the
sample required is orders of magnitude less than
traditional methods. In this work, we aim to
characterize the system operating parameters for
optimal use and consistency.
When using the QCM technique there is a significant
amount of data points to take into account for graphing
and analysis. After data collection from a flow run,
there still needs to be the graphing and analysis of data
in a spreadsheet program to visualize the data and
determine the regions of interest used to account for
total mass dissolution rate without interference from
other variables put into the system at the time of
testing. Thus to increase efficiency and accuracy, the
regions are dynamically determined from the moment
of water application to the quartz crystal and the
approximate fill time of the 150uL flow cell when the
interference of filling is overshadowed by pure mass
dissolution of the drug.
Dean Emeritus Ravi Jain
Professor Xin Guo
Professor Bhaskara Jasti
Li, Guo, & Jasti Research Groups
Janpierre Bonoan
Development of a Drug Dissolution Test and Automated
Analysis Method Using a Quartz Crystal Microbalance
Joshua Arucan, Shelly Gulati
School of Engineering and Computer Science
University of the Pacific, Stockton, CAIntroduction
Acknowledgements
Dissolution Rate
Theory
The QCM oscillates a quartz crystal to its resonant
frequency. The applied mass changes this resonant
frequency and the relationship is described by the
Sauerbrey equation,
Materials & Methods
References
1. Sauerbrey, G. Z.Phys. 1959,755, 206.
2. Frequency of a quartz microbalance in contact with
liquid Kanazawa, K. and Gordon, J. Analytical
Chemistry 1985 57 (8), 1770-1771
3. Drug dissolution rate measurements – evaluation
of the rotating disc method. Kaunisto, E. et al.
Pharmaceutical Development and Technology. 2009
14:4, 400-408
Δfm = Cf Δm
frequency
change
sensitivity factor
(property of quartz)
change in mass
per unit area
Apparatus
• Stanford Research Systems QCM200
• Sensitive to mass changes as low as 18ng/cm2
• Flow rates of up to 1000 μl/min
Syringe pump
drives flow
Flow cell
Quartz crystal
with drug film
inside housing
QCM system
connected to
computer for data
acquisition
-1500
-1000
-500
0
500
1000
1500
2000
2500
0 25 50 75 100 125 150
∆F,Hz
Time, s
ΔF drops due to
contact with water
(Region II)
ΔF rises as drug
dissolves
(Region III)
ΔF reaches plateau
at full dissolution
(Region III)
Stable before
water contact
(Region I)
Frequency shift profile for dissolution of 150 μg
benzoic acid by water at 1000 μL/min
Results
Sample drug: Benzoic acid was selected because its
dissolution rate in water has been previously
characterized by traditional dissolution methods.
Film preparation: Benzoic acid was dissolved in
isopropyl alcohol. A small volume of the solution of
known molarity was applied to the quartz crystal. The
isopropyl alcohol evaporated readily and benzoic acid
recrystallized onto the surface of the quartz crystal
(see figures on middle panel).
Dissolution Testing: The quartz crystal with drug film
was loaded onto the quartz crystal microbalance with
an attached flow cell. Deionized water was flowed into
the system via syringe pump. As the benzoic acid
dissolved, the change of the quartz crystal’s resonant
frequency with time was visualized and collected by
the LabVIEW interface. The frequency signal
corresponding to mass dissolution is isolated and
converted to % mass dissolved.
Future Work
• Characterize dissolution rate of benzoic acid over
wide range of flow rates and compare with
conventional methods.
• Conduct dissolution testing of other sample drugs.
• Determine how fast tests can be done to avoid
overworking the quartz crystal.
• Determine through pharmacokinetic theory a full
dissolution profile for testing drugs
The program itself dynamically looks to find the regions
defined by previous results:
To support finding these regions, a resistance graph is used
to determine the start and end points. Then using user
given variables for flow rate and flow cell volume, it
calculates how long it should take to fill the flow cell. This
determines the start time of Region III and allows for mass
dissolution calculations to begin.
• Region I is the Recrystallized mass on quartz crystal
before contact with water
• Region II is the unstable region where water contact
and dissolution are happening at the same time
• Region III is where there is solely mass dissolution
0
20
40
60
80
100
120
0 100 200 300 400 500 600
%MassDissolved
Time(s)
Percent Mass Dissolution graph as compared to time from a test using
150μg of Benzoic acid/2μL Isopropanol at 100μL/min flow rate
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 200 400 600 800 1000 1200
%mass/s
Flow Rate (μL/min)
Manual Analysis Computerized Analysis
% Mass dissolved per second compared to flow rate graph using 100μg
Benzoic Acid/2μL Isopropanol solution. At 1000μL/min, both data points
occupy the same % mass/s value.
Manual Analysis Computerized Analysis
Flow Rate (μL/min) 1000 100 50 1000 100 50
Trial 1 (% mass/s) 4.805 1.367 2.005 3.528 N/A 2.299
Trial 2 (% mass/s) 4.382 3.105 1.248 3.707 1.882 1.880
Trial 3 (% mass/s) 3.844 2.455 1.680 4.711 2.018 2.020
Trial 4 (% mass/s) 3.083 1.178 1.327 4.069 1.157 1.679
Average (% mass/s) 4.029 2.026 1.565 4.0038 1.6857 1.9695
STD 0.743 0.913 0.348 0.522 0.463 0.260
Table comparing original thesis data to computerized data.
• Computerized analysis data matches Manual Analysis data.
• Manual analysis data contained higher standard deviation values,
which indicates that the computerized analysis is more precise at
determining regions.
• Due to the speed of computerized analysis new issues with QCM
testing have appeared.
• High volume testing creates errors in quartz crystal causing it to
not reach oscillating frequency.
• Quartz crystal has finite life of about 50 tests.
Summary of Findings