Recomendados
Más contenido relacionado
La actualidad más candente
La actualidad más candente (18)
Destacado
Destacado (14)
Similar a Controlling Crystallization of Acetaminophen via Polymeric Films and Surfactants
Similar a Controlling Crystallization of Acetaminophen via Polymeric Films and Surfactants (20)
Controlling Crystallization of Acetaminophen via Polymeric Films and Surfactants
- 2. Properties can be used to change manufacturing process (filtration, milling, drying, etc.) and dissolution rates Streamlining the manufacturing process means less expensive drugs for consumers millin g granula tion
- 3. Two step process 1. Nucleation- creation of new phase (i.e. liquid to solid) 2. Crystal growth Crystal Growth Saturated solution Create supersaturation and formation of nuclei One of the most important means of controlling crystallization is nucleation
- 5. Supersaturation state of solution that contains more dissolved solute than could be dissolved under normal circumstances Super cooling process of lowering temperatures below freezing without solvent solidifying Heterogeneous nucleation the method used in our experiments
- 6. Almost all crystallization processes occur heterogeneously What has been done before: SAM (self-assembled monolayer) ▪ Inefficient method hom het evaporation
- 7. Biocompatibility Easy manufacturing Polymeric films contain immiscibility caused by micelle formation Micelles act as nucleation sites for acetaminophen
- 9. Nucleation mechanism was elucidated by identifying which crystal face was in contact with the polymer surface. Preferred orientation exhibited in the PXRD imply preferential nucleation face (02 2) AAP Form I ( No Preferred Orientation) AAP Form I Preferred Orientation in the presence of Na CMC film with SPAN 80
- 10. [10-1] [022] Both Na ALG F108 21% 17% 62% Na ALG PAA 10% 21% 69% Na CMC 7% 54% 39% Na CMC F108 48% 0% 51% Na CMC SPAN 80 0% 93% 7%
- 11. Na CMC Na CMC F108 Na CMC SPAN80 Na ALG F108 Na ALG PAA
- 12. Theoretical C/O Ratio Experimental C/O Ratio Na ALG F108 1~1.09 1.70±0.07 Na ALG PAA 1~1.03 1.94±0.1 Na CMC 1 1.54±0.05 Na CMC F108 1~1.45 2.16±0.12 Na CMC SPAN 80 1~1.52 (FLAT) 2.67±0.41 (Grey Patch) 4.65±1.59 C/O Ratio CMC 1 F108 2-3 SPAN 80 4 ALG 1 PAA 1.5
- 13. SPAN 80 Concentration (g/100g) [10-1] [022] Both 0.405 0% 100% 0% 0.2025 0% 99% 1% 0.102 0% 93% 7% 0.0506 0% 99% 1% 0.038 0% 98% 2% 0.032 2% 79% 19% 0.018 0% 80% 20% 0.008 0% 76% 24% 0.0054 2% 63% 35% 63 76 80 79 98 99 93 99 100 0 10 20 30 40 50 60 70 80 90 100 0.0054 0.008 0.018 0.032 0.038 0.0506 0.102 0.2025 0.405 ProbabilityofNucleationPlaneat(022) SPAN Concentration (g/100g)
- 14. 0 10 20 30 40 50 60 70 80 90 100 0 0.2 0.4 0.6 0.8 1 ProbabilityofNucleationon(022)Face Concentration of F127 (g/100g) Probability of Nucleation on (022) Face 0 10 20 30 40 50 60 70 80 90 100 0 0.01 0.02 0.03 0.04 0.05 0.06 robabilityofNucleationon(022)Face Concentration of F127 (g/100g) Probability of Nucleation on (022) Face [10-1] [022] Both 0.81 25 24 51 0.05 1 80 19 0.01 3 92 5 0.005 0 94 6 0.001 12 39 49 Probably, there are four phases in F127 controlling nucleation • Phase 1: after initial addition of small amount of F127, it starts to lose selectivity • Phase 2: selectivity begins to increase via the addition of more F127. • Phase 3: shows exclusive control of nucleation within a range • Phase 4: when the concentration of micelle is too high, it starts to loose the selectivity.
- 15. 0.81 0.05 0.01 0.005 0.001
- 16. C/O Ratio 0.81 1.91±0.03 0.05 1.40±0.04 0.01 1.48±0.05 0.005 1.36±0.01 0.001 1.33±.0.02
- 17. 0.81 0.05 0.01 0.005 0.001
- 18. F127 forms globular micelle in size range of 68- 70 nm Difficult to see under the microscope
- 19. Size of the micelle formed by F127 and SPAN 80 are different. Micelle size of F127 is much smaller than SPAN 80. So we rarely can see under microscope. F127 and F108 have similar structures, but F127 can control the nucleation mechanism because F127 has a lower critical micelle concentration so that F127 can form micelle at a concentration we can use. The ability to form micelles and the number of micelles that can be formed by the surfactant is critical to control the nucleation mechanism.
- 20. Methodology for analyzing critical micelle concentration Choose another surfactant to test our hypothesis
- 21. Supervisor: Dr. Keith Chadwick Graduate student: Jing Ling Chadwick Lab group
- 22. Questions?
Notas del editor
- First, I will introduce the importance of crystallization. Crystallization, as you can see from the flow chart, is the first step in the manufacturing process and It is the most important unit operation for separation and purification. This is because crystallization determines the properties of the crystal such as—purity, size and shape distribution. Theses properties, in turn, can affect the downstream processing procedures—like filtration/drying, milling, blending, etc. etc. Therefore, finding a way to control crystallization can lead to a more streamlined and efficient manufacturing process, which ultimately means more inexpensive drugs for consumers.
- The crystallization process consists of two major events—nucleation and crystal growth. The first stage in crystal formation is nucleation. Nucleation is a change in state that occurs around certain focal points i.e. nuclei And crystal growth is essentially the growth of the nuclei. Both of these events affect the size and shapes of the crystals obtained. Therefore one of the most important means of controlling crystallization is nucleation.
- The nucleation process can be classified as either primary or secondary. Secondary nucleation requires seed crystals or existing crystals to induce crystal growth whereas that primary nucleation happens spontaneously without the presence of pre-existing crystals. Under primary there is heterogeneous and homogeneous nucleation. Heterogeneous nucleation occurs when crystal growth happens on a foreign surface like for example dust particles or the sides of the container and homogeneous nucleation, which is much more rare than heterogeneous nucleation because it occurs without the presence or influence of foreign surfaces.
- There are several methods to control nucleation. One of which is supersaturation Another is super cooling, which is the process of lowering the temperature below freezing while still having the solvent remain a liquid, the solvent can then be induced to crystal with the addition of a seed crystal, which acts as the nucleus People have also used probes to detect crystal size and by detecting for uniform crystal size, they can know how to change the parameters (cooling rate or temperature, etc.) to get uniform crystal size And also, heterogeneous nucleation, which is the method our experiment uses to control nucleation
- Almost all crystallization processes occur heterogeneously. This is due to the fact that they are more thermodynamically favored than homogeneous nucleation. The surfaces or impurities that nucleation occurs on acts to lower the activation energy for nucleation below that of homogeneous nucleation. A method that has been used before to control crystal nucleation is SAM or self-assembled monolayers. In this method a metal substrate having areas of different nucleating properties, pictured by the blue dots and then are immersed in a solvent and allowed to evaporate. As you can imagine taking the time to make each individual island can very inefficient.
- Which is why I will introduce the advantages to using our method. Firstly, it is biocompatible, with the self-assembled monolayers they often used metals substrates in their procedure which is, obviously, not digestible by people and also not approved by the FDA. It’s also easier to manufacture, unlike with the self-assembled monolayers where you have to take the time to make each individual island (or nucleation site) on the substrate with our method all you have to do is the cast a film. And lastly, the polymeric films contain immiscibility generated by micelle formation, and the micelles, similarly to sam’s islands will act as nucleation sites
- The methodology to creating the polymeric films is very simple. You first start out by pouring the polymer solution onto the substrate where you then drag the film caster (pictured here) across the substrate to ensure that the film has a uniform thickness and then you allow it air dry. Once dried, you dropped a supersaturated solution of acetaminophen on the film and allowed it to air dry before Jing x-rayed the samples.
- PXRD acronym? powder xray diffraction Nucleation mechanism is defined by which crystal face is nucleated on the polymer surface. We found that AAP form I: powder showed no preferred orientation and we can see that because there are multiple peaks of similar intensity. However, we add Na CMC (sodium carboxymethyl cellulose) and the surfactant, span 80 we can see the there is a strong peak indicating preferred orientation towards the 022 face Preferred orientation is the way to find out which face nucleates on the surface (how we study nucleation mechanism) arises when crystals have a stronger tendency to be oriented a certain way, or ways, than all other ways.
- PET (Poly ester) Na CMC, Na CMC F108, Na CMC span 80, Na alginate with F108 and Na alginate with PAA (or poly acrylic acid)) While 4 out of the 5 films showed little to moderate probability to nucleate on the 022 face, the film containing the surfactant span 80 showed a 93% probability to nucleate on 022 face BOTH: two peaks then the ratio to one another is less than 2 then we say that they are both preferred Have two peaks, if the peaks ratio to one another is greater than 2 then we say it prefers to nucleate on one face
- When looking at the surface chemistry of the films we can see that 4 out of the 5 films exhibit uniform surface chemistry while span 80 has these grey bumps, which we are the micelles
- By looking at the c/o ratios of the surfactants we see that span 80 has the highest ratio, while the other surfactants have a low ratio. Furthermore, the grey patches/bumps (which are the surfactant rich areas) have a high c/o ratio than the flat areas
- From this data we can see that the higher the concentration of span 80 the greater probability to nucleate on the 022 face Also, we can see that you have to be above a certain range in order to achieve complete selectivity
- Another surfactant we analyzed was F127. From our experiment we think that there are four phases in F127 controlling nucleation Phase 1: Phase 1 shows that after a small addition of F127, selectivity is decreased Phase 2: Phase 2 shows that the selectivity is increasing by the addition of more F127, but the number of micelles is still not enough for complete control of nucleation Phase 3: The 3rd phase shows exclusive control of nucleation within a certain range, possibly meaning that the number of micelles has reached the optimum level to control nucleation Phase 4: This phase shows (as shown by the tail end of this graph), that when the number of micelles is too high, selectivity gets lost
- (SEM) Scanning electron microscope These images show the surface of the F127 film at 5 different concentrations to be uniform and without bumps—which is very different compared to when we looked at the surface of span 80
- EDS acronym (same as EDX) This chart shows a direct relationship between the concentration of F127 and C/O ratio. As we decreased the amount of F127 the C/O ratio decreased.
- These are microscope images of the varying concentrations of F127 polymer solution and as you can see there are no micelles visible, even at high concentrations of F127.
- And this is because the micelles that F127 form are very small and is difficult to see under the microscope. Whereas with Span 80, the micelles are clearly visible and that is because the micelles of span 80 are in the micrometer range while f127 is nanometer range CMC of F127 is higher so you need to add more of it to see micelles whereas CMC of span 80 is lower so you need to add less surfactant
- Firstly, the size of the micelles formed by f127 is much smaller than that of span80, which makes the micelles hard to see under a microscope. Secondly, F127 and F108 have similar structures, but F127 can control nucleation mechanism because it has a lower critical micelle concentration, meaning it can form micelles at the concentrations that we study Lastly, the ability to form micelles and the number of micelles that can be formed by the surfactant are both critical to control the nucleation mechanism
- Some areas of future work include finding another method for analyzing the critical micelle concentration and choosing another surfactant to test to see whether or not our hypothesis is consistent.