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Q&A: Formulation Considerations for development of Ternary Solid Dispersions

Dr. Harsh Chauhan, Creighton University

Q: What do you mean by precipitation of indomethacin? The objective not clear and what is the inference of this.
A: Precipitation of indomethacin is referred to as pure indomethacin precipitation when its added to phosphate buffer. The study is used as control i.e. precipitation of indomethacin in absence of polymer.

Q: Is there a possibility to quantify the % of the drug interacted with each polymer in TSD. for example the IND-PVP-Eudragit E system.
A: It can be but not by using IR/ Raman techniques, we used. The peak shifts were very small and were not concentration dependent. Techniques like ssNMR, solution based techniques might be used to quantify the interactions. 

Q: What cooling rate do you use for the crystallization tendency experiments?
A: We used 2-5C/ minutes as our cooling rate for crystallization tendency experiments. 

Q: When you talk about precipitation inhibition, with the ternary system, do you get clear solution or colloidal solution? How you corelate the in-vitro solution behavior with in-vivo drug absorption?
A:
We got clear solutions but after precipitation it turned into a coarse dispersion. We didn’t carried out in-vivo drug absorption experiments. 

Q: Did you perform your DSC data on physical mixtures or did you process them in advance? Nucleation is more likely in physical mixtures than in homgeneously dispersed systems.
A:
For crystallization tendency and miscibility studies we used physical mixtures in various heat-cool-heat cycles. We also characterized dispersions for Tg, crystallization, any other endothermic-exothermic events.  

Q: On slide 30, how do you untangle the observation of crystallization during the evaporation step from acetone from the stabilization offered by the hydrophilic polymer. nucleation could be happening purely from the evaporation of acetone.
A: Agreed. We wanted to study the crystallization (nucleation) in absence and presence of polymers. We wanted to explore the feasibility of using it as quick study to identify polymers inhibiting drug nucleation.

Q: Are there any compound characteristics which make it impossible to stabilize in amorphous form using ternary dispersions?
A: There are no specific characteristics but sometimes achieving the correct balance in terms of solubility and stability increase is difficult. We have observed good long term stability of certain compounds but unfortunately the solubility increase was not sufficient despite >90% polymer concentration.

Q: Indomethacin has been tried in many classical ways like solid dispersion, etc .. what is the difference and significance of doing the same old drug in improving the solubility and of course bioavailability?
A: Indomethacin was used as a model compound. We prepared anti-tubercular/ anti-cancer combinations base don our understanding of indomethacin system.

Q: Can the effect of adding a third component on drug-polymer interaction and hence the stability of the Binary ASD be predicted?
A: Yes, the effect can be because of drug-polymer interactions but its difficult to predict. We have limited success based on various interaction parameters. It will be a great next step for the ternary systems if we can predict.

Q: Can you tell us something about the PEG Dispersions and the stability related issues?
A: We did very limited studies on PEG based dispersions and mostly used it as a control. Since, PEG is a crystalline polymer with low melting point (60C or so), the dispersions were difficult to characterized as amorphous. We observed crystalline peaks and for the drugs we used it was not stable (amorphous form). However, PEG can be a good polymer for creating eutectic, nono-crystalline/ molecularly dispersed drug in crystalline matrix.

Q: Are there any commercial products in market utilizing ternary polymer amorphous dispersion approach?
A: No, but there are few systems in clinical trials.

Q: So does molecular modeling predict tractable polymers for specific drugs?
A: We use molecular modeling in conjunction with other miscibility/ precipitation studies to better select most optimum polymer. In our experience, molecular modeling alone cant be used to accurately predict most optimum polymer for specific drugs. 

Q: How do you test miscibility in the ternary system? You are right about the lack of predictability of theoretical models. Then, how do you ensure that the drug will not crystallize out upon long-term stability?
A: Melting point depression, drug crystallization tendency, miscibility studies using MDSC can be used to give some insight into long term stability. If we have low drug loading and if polymer showed strong interactions with the drug, the system can be assumed to pose no stability challenges. However, actual studies or accelerated studies are required to confirm.  

Q: With ASD, what is the max oral dosing that has been achieved for BCS class IV drugs?
A: We are not aware of max oral dosing for Class IV drugs. Our studies have mostly focused on Class II drugs.

Q: You mentioned during your talk that in the case of BCS IV drugs, Amorphous Solid Dispersions affect only solubility, not permeability which is mediated by P-glycoprotein (P-gp). However, surfactants and polymers in Amorphous Solid Dispersions have been reported to inhibit P-gp in vitro. Please elaborate. Thanks.
A: You are correct. I don’t recall making the statement but its wrong. Appropriate polymers and surfactant can affect both solubility and permeability.

Q: What are the main mechanisms by which a good “parachute” phase can be achieved?
A: Polymers effect on crystal growth, high molecular weight, stronger interactions between drug and polymer are some of the mechanism for a good parachute.

Q: Have you tried any high Tg lipids >50C and formualted into successful ASDs?
A: No, we haven’t tried high Tg lipids.

Q: How can we quickly scan the most appropriate drug-polymer-surfactant with so many polymer or surfactant options without large scale manufacturing? Have you tried any high throughput methods?
A:
Yes, we have tried precipitation studies in a 96 well plate and thin film casting method with good success to identify most appropriate polymers/ surfactants.

Q: XRD studies also to be performed simultaneously with DSC… to find the thermodynamic stability… But how best we perform stability studies. And is a 3 month study sufficient?
A:
Usually, 3 months studies are no sufficient. Accelerated stability studies at high RH and T are recommended. Personally, I will recommend carrying out at least XRD, DSC and in-vitro release studies throughout the stability testing to assure of good stability and performance. During initial ASD development for animal tox studies/ preformulations stages 15 days-3 months studies are usually sufficient.

Q: Is hot stage microscopic evaluation will give any useful information on ternary solid dispersion? considering individual melting points by polymers and drug substance?
A:
Unfortunately, not. Tg/ Tm of one component will affect the subsequent Tm and it will be difficult to get any quantitative information.

Q: Have you tried using drug- polymer lipid – combination as amorphous solid dispersion approach for enhancing bioavailability and stability?
A:
We tried a few combination but stability was a concern due to low Tm of lipids.

Q: Is there a possibility to quantify the % of the drug interacted with each polymer in TSD. For example, the IND-PVP-Eudragit E system.
A:
It will be difficult but ssNMR can be tried. We tried using IR/ Raman but getting quantifiable interactions was difficult.

Q: You mentioned during your talk that in the case of BCS IV drugs, Amorphous Solid Dispersions affect only solubility, not permeability which is mediated by P-glycoprotein (P-gp). However, surfactants and polymers in Amorphous Solid Dispersions have been reported to inhibit P-gp in vitro. Please elaborate.
A:
You are correct. I don’t recall making the statement but its wrong. Appropriate polymers and surfactant can affect both solubility and permeability.

Q: What is the relationship between solid dispersion and bioavailability?
A:
Solid dispersion is an approach to enhance solubility leading to higher bioavailability of poorly soluble compounds.