Dr. Changquan Calvin Sun, University of Minnesota (UMN)
Q: At what batch size one should start blend uniformity studies?
A: The CU issue should be looked at as soon as possible, even for a small batch.
Q: What is impact of particle shape on flow?
A: In generally, more elongated particles tend to flow worse if everything is the same.
Q: What do you recommend to improve needle like particle flow?
A: granulation if API crystals cannot be modified. If it is possible to engineer crystals, consider spherical crystallization or reduce aspect ratio by controlling crystallization conditions.
Q: What influence has the crystal particle size in this optimization process?
A: Keep an eye on the particle size of the API you use in the formulation. When particle size changes, its effect on flow or compaction properties can be qualitatively predicted. At some point, particle size effect should be studied once a preliminary formulation has been identified.
Q: What is your approach for taste assessment?
A: Assessment by a taste panel is the most reliable.
Q: Slide 18 Should you associate MS Tetrahedron with Manufacuring classification System ( MCS)
A: Yes, they can be integrated to guide the development of a new drug.
Q: What specific measures can be taken to control the process induced polymorphic changes in API, coformer or excipient components of a tablet formulation?
A: In generally, polymorph changes can be controlled most effectively by controlling compaction pressure. However, depending on cases, other techniques can be considered.
Q: What process do you use for selecting and optimizing tablet filler composition for IR tablets? Is it tailored to the API properties?
A: Yes. The properties of the final formulation should be well defined. Then, excipient can be chosen based on the properties of the API and its dose.
Q: How do you go about choosing the ratio of the excipients when conducting the formulation screen?
A: This can be guided by predictive measurements for specific properties. One must have a clear understanding of properties of excipients too. The first formulation can be an educated guess. The improved formulation needs to be based on knowledge of the first formulation.
Q: In the production of your novel API forms, did you conduct any post-crystallization particle size control? If so, how did you do that in a material sparing manner?
A: We milled large crystals before using them in formulations.
Q: Has any Pilot bio been done?
A: No.
Q: Low dose drugs have content uniformity issue. My question is to you that how to solve this problem?
A: See https://doi.org/10.1016/j.xphs.2017.03.005
Q: Was this work done on a single punch press or multi head press?
A: It was done on a compaction simulato.
Q: If a high dose drug (water soluble) has small half life. How can we sustain its release?
A: Consider sustained release formulation technologies.
Q: If we are preparing a tablet containing drug loaded microspheres, how can we find compression force window?
A: The thought process would be the same as the examples I gave.
Q: Shear cell is that the FT4 by Freeman Tech?
A: We used Schulze shear cell. The size of shear cell can influence the flowability data. Expect a paper on this from our lab soon.
Q: Could you please elaborate on the use of GLA in GI PPT inhibition? It is nice to use same common ion but what do you suggest if IDD amount is exceeded while doing this?
A: Not sure what IDD is. One needs to observe all possible limitations and design formulations to deliver the formulation that satisfy all of them.
Q: Could you please elaborate on the tabletibilty profile? How do you measure the tensile strength?
A: You can make tablets under a number of pressures and plot tensile strength vs. pressure to get the tabletability profile. Tensile strength can be calculated from breaking force and dimensions of a tablet. Different equations are needed for different shapes.
Q: In a tablet, whether the idea situation in the tablet is for API being as a crystal status or in a amorphous status? which is better and why?
A: It depends. Crystals have better stability, but amorphous solids have higher solubility. However, the range of each properties within crystalline and amorphous groups remains large. Hence, they overlap. We cannot categorically state one class of materials is better than the other.
Q: When do you recommend running compatibility studies? Is it better to run on binary combinations or wait for final tablet ingredients to be identified first?
A: Run binary compatibility first. Information from that study informs the formulation development. The other way is also fine, but the risk is higher. If incompatibility is observed in the formulation, an investigation is needed to overcome the problem. If no stability issue, you can save the work of doing binary mixtures. Once can also predict chemical stability based on the molecular structure of your API.
Q: For Metforman (slide 15-16) what was your batch size to use only 50 g of API?
A: 10-20g.
Q: What is the largest scale for case 1?
A: 20 g or less
Q: For case 1, can you comment on the crystal engineering aspect of MetHCL?
A: This was addressed in the talk.
Q: How do you measure the flowability Index?
A: This was addressed in the talk. See https://doi.org/10.1016/j.powtec.2015.11.044 for more details.
Q: Can the salt formation be done in a pharmacy setting? In other words, can it be done via extemporaneous compounding by pharmacists?
A: unlikely
