2. The process of drug manufacturing can be
broken down into a series of steps called unit
operations
Traditional Manufacturing:
crystallization filtration/
drying
milling blending granulation
tableting,
capsuling,
etc.
3. Drug manufacturing (especially on a large
scale) is labor intensive, inefficient, and costly
The current global environment is forcing
pharmaceutical companies to improve
efficiency and reduce costs
4. Problem: in nature crystals commonly form needles,
which is disadvantageous
Spherical particles are the ideal shape for manufacturing in terms of
flow and compression
Solution: developing spherical crystallization
method is a way resolve this issue
5. Emulsion crystallization is used as a means to
control particle properties
Confinement of drug in oil droplets allows a control of the
properties of crystalline material (makes spheres)
Emulsion crystallization of glycine SEM -- Final crystals of glycine
6. For many systems emulsion crystallization is not
ideal
Many steps and parameters (i.e. stirring rate,
temperature, amount of emulsifier, etc.) are
involved and need to be accounted for
Emulsion crystallization of ephedrine Final crystals of ephedrine emulsion
8. Attempts to resolve two problems
Problem 1: shape
Spherical particles are advantageous for
manufacturing but crystals are not found this way
in nature
Problem 2: reduce number of unit operations
manufacturing process is complex and expensive
9. Hydrophilic solvent on hydrophobic
surface (or vice versa)
Print, evaporation, particles roll
Drop 3ul solution onto polyester
substrate
20g glucose + 100mg CMD + 10mL H2O
Once crystallized particles are easily
moveable
Side profile of CMD+ glucose on substrate
Printed droplets evaporating
11. Discover which formulations work best in aqueous
solutions
Tested two different active ingredients (Proline and CMD)
Learn which hydrophobic surface works the best
1022 and PTFE (reusable)
Non-stick surface will allow for easy collection of particles
15. Tomography is a technique used to display a cross
section of a solid object
X-ray computed tomography used X-rays to create
cross sections of an object, which can then be used
to recreate a virtual model (3-D structure)
16. Shape
Particle size and shape can be controlled
by controlling droplet size
▪ CMD + glucose diameter: 1980 ± 70 μm
Unit operations
Refine process to reduce amount of steps and directly start
tableting, capsuling, filling, etc.
Drop
crystallization of
API/Excipient
Solution
Tableting,
capsuling, filling
Crystallized droplet
17. Emulsion crystallization do not work on many
systems
However, when using formulations in drop
crystallization experiment, the systems
crystallized and formed spherical particles
Drop crystallization works on a wide range of
drug compounds
18. Bioavailability testing (dissolution properties)
Drug has to dissolve before it is absorbed by body
Put particle (loaded with drug) in buffer that
simulates body’s environment
Switch to hydrophobic solvents and
hydrophilic surfaces
Most drugs are not soluble in water (inefficient
drug loadings)
19. Project Members:
Jing Ling (graduate student)
Elaine Jiang (undergraduate)
Chadwick Lab Group:
Supervisor:
• Dr. Keith Chadwick
Editor's Notes
To start off my presentation, I just wanted to give a little background info into pharmaceutical manufacturing. Drug manufacturing –or the process of drug manufacturing can be broken down into a series of steps called unit operations
And the traditional manufacturing steps include: crystallization, filtration or drying (to remove the entrained solvent), milling (done to achieve desired size of particle distribution), blending (mix excipient and API), granulation (which distributes the drugs uniformly in the blend), and finally tableting and capsuling
From the flow diagram you guys can probably tell that the traditional method of drug manufacturing is very labor intensive, inefficient (time consuming), and costly
Because of these reasons much of the global environment has been pushing pharmaceutical companies to improve efficiency and reduce costs
However, there are some barriers that prevent pharmaceutical companies from refining these steps. So what are some of those problems?
In nature crystals commonly form needles (this is referring to specifically organic compounds) some examples of what I mean by needle like crystals are shown in these two images
Needle-like crystals pose a problem because the ideal shape for manufacturing—in terms of flow and compression is actually spherical particles
But the good news is that there is a the solution to this problem! And that is to use spherical crystallization methods
emulsion crystallization is very commonly used as a means to control particle properties
This is done by creating an oil and water emulsion, or in other words confining the drug in oil droplets
The bottom left image represents an emulsion of glycine, and the image to the right is an SEM of the final product. As you can see, in this experiment the emulsion was successful in forming spherical particles.
However, crystal emulsion is not always ideal.
For many systems crystal emulsion does not form spherical particles
Emulsions have complex procedures that require many steps and in addition the experimenter has to take into account many different parameters such stirring rate, temperature, amount of emulsifier, etc. etc.
In contrast to the two images on the previous slide, these images represent an emulsion that did not work…as you can see the final crystals are not spherical
These images are actually of emulsions that were attempted by Dr. Chadwick and I at the beginning of the year, and this emulsion did not work in this case either
Because crystal emulsions are not universal to all systems there needs to be another method to create spherical particles, and this is where drop crystallization comes into the picture
This project attempts to resolves two problems
1) Having to do with the shape of the particle because the aim is to make spherical particles that are advantageous for manufacturing and secondly, not only do we want to create a shape that is ideal for manufacturing, we want reduce the number of unit operations to make the process more streamlined which in turn improve efficiency and reduce costs
The methodology in drop crystallization is very simple.
It starts with either using a hydrophobic solvent on a hydrophilic surface or, in our case, a hydrophilic solvent on a very hydrophobic surface.
Once that is established, there are sort of three basic steps involved which are printing, evaporation, and particles rolling
The printing step is when you drop 3 microliters of the solution onto the surface and since we are using a hydrophilic solvent on a hydrophobic surface the droplet should ball up on the surface of the substrate as shown by the image on the left
The evaporation step, shown by the picture on the right, allows the crystals to dry and crystallize, and once crystallized the particles are easily movable.
This is just a little video showing how easily the particles can be moved, there’s a little bit of resistance, but for the most part they can be pushed around with minimal effort
some specific aims of drop crystallization include:
Discovering which formulations worked best in aqueous solutions, I tested both proline and CMD, but I found that proline gave more flat and porous particles whereas CMD yielded more smooth and rounded particles
Also, we would like to learn which hydrophobic surface works best with the formulations. Again, I tested two surfaces 1022 and PTFE. Overall, I found that the PTFE yielded more compact particles and allowed for easier mobility than the 1022 surface. In addition, it’s also reusable which could also be beneficial in terms of cost!
This is an SEM (scanning electromicroscope still use x-rays) of a glucose/CMD particle
The leftmost image shows the particle at a low magnification, as you can see the surface is very smooth looking but as the magnification increases in the rightmost image the surface becomes very rough and bumpy looking
Powder x-ray diffraction shows us the most stable polymorphs
Looking at this graph you can see the glucose has two polymorphs and CMD as three
By looking at which peaks are aligned, you and figure out which polymorph is the most stable
In this case the most stable polymorphs are beta glucose and CMD A
Understanding the polymorph is important in manufacturing because polymorphs can transform and reduce bioavailability over time (more specifically the dissolution/solubility properties of drug)
CMDC: Stable or meta-stable?
The X-rays, in contrast to powder x-ray diffractions, are absorbed in this method
Dark regions correspond to where the x-rays are absorb whereas the white spaces correspond to where the x-rays pass through the particle
Putting all of this information together we can see that a CMD/glucose bead is porous (where the white spaces are) and more dense and smooth on the surface because the cross section is darker around the edges of the sphere
Just a little fun fact: this is the same method that is used in CT scans
Can’t distinguish where CMD and glucose are because they have the same densities and absorb the same amount of x-rays
This slide serves to summarize what this project achieves. In terms of shape this experiment is successful because the particle shape and size can be controlled by controlling the droplet size.
And lastly, if you remember the flow chart I showed you at the beginning of the presentation, how tedious and complex it was to get to the final stage of tableting and capsuling. This experiment refines that process so that you only need to do the drop crystallization of the API/excipient solution (also known as the printing step) and once the droplet dries you can start directly tableting and capsuling!
In conclusion:
Emulsion crystallizations do not work on many systems (i.e the CMD + PAA + glucose)
But when using the same or similar formulations in drop crystallization experiment, the systems crystallized and formed spherical particles
Overall, drop crystallization works on a wide range of drug compounds as well as streamlines unit operations to increase efficiency in manufacturing
Some potential avenues that this project could be applied to is bioavailability testing (pertains more specifically to dissolution properties)
After a tableting, manufacturers need to test how well a drug is absorbed by the body, but before a drug is absorbed it needs to be dissolved. Dissolution testing puts a particle (loaded with a particular drug of interest) into buffer solution that simulates the body’s environment to measure how well the drug dissolves
For all my experiments, I used a hydrophilic solvent on a hydrophobic surface, but in reality most drugs are not soluble in water, which is why for future work, it would be useful to switch to using hydrophobic solvents on hydrophilic solvents
