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Amphiphilic Polymers: Crystallization-assisted Self-assembly

and Applications in Pharmaceutical Formulation





Ligeng Yin




Marc A. Hillmyer, Advisor April, 2013 © Ligeng Yin 2013 i Acknowledgements First and foremost, I would like to thank my advisor Prof. Marc Hillmyer. His guidance and continuous support not only helped me improve scientific conduct, but also triggered me to be passionate about polymer science and further take full responsibility of research projects. Besides, Marc was always very open-minded, which granted me much freedom in exploring different areas and pursuing what I love.

I was greatly blessed to spend the last five years and a half in the Polymer Group at University of Minnesota. I have been continuously growing in the friendly and collaborative atmosphere. In particular, I would like to thank Prof. Tim Lodge for his help on small-angle neutron scattering including data acquisition, treatment, and interpretation. I thank Prof. Theresa Reineke for her valuable biological perspective on macromolecules in biological studies. I also thank many other members for the priceless daily interactions through whether training on instrument, sharing chemicals, or debating on specific questions: Dr. Sara Arvidson, Dr. Zhifeng Bai, Dr. Liang Chen, Dr. Soohyung Choi, Molly Dalsin, Dr. Gina Fiore, Dr. William Gramlich, Yuanyan Gu, Dr. Elizabeth Jackson, Dr. Justin Kennemur, Dr. Shingo Kobayashi, Dr. Hau-Nan Lee, Dr. Sangwoo Lee, Dr. Chun Liu, Dr. Ameara Mansour, Mark Martello, Dr. Henry Martinez, Maria Miranda, Dr. Adam Moughton, Dr. Tushar Navale, Matthew Petersen, Dr. Louis Pitet, Dr. Yang Qin, Ralm Ricarte, Dr. Megan Robertson, Dr. Myungeun Seo, Dr. Jihoon Shin, Joshua Speros, Swapnil Tale, Dr. Rajiv Taribagil, Grayce Theryo, Dr. Eric Todd, Dr.

Athanasios Touris, Yaoying Wu, Dr. Jihua Zhang, and Can Zhou.

ii I thank Dr. Steve Guillaudeu, Dr. Bob Schmitt, and Dr. Trey Porter at The Dow Chemical Company, whose comments during monthly meetings and through daily emails helped me pick up the cellulosics project and further make progress. I also thank Dr.

Antons Sizovs at Virginia Tech for providing a trimethylsilyl-protected glucose methacrylamide monomer with very high purity.

Much of the progress cannot be achieved without the staff’s diligent work on maintaining the instrument and expert advice on learning a technique. I thank Dr. Letitia Yao, Dr. Wei Zhang, Dr. Bob Hafner, Chris Frethem, and David Giles at Minnesota, Dr.

Yun Liu and Dr. Steve Kline at NIST, and Dr. Steve Weigand at Argonne National Laboratory.

Last but not least, I thank my wife, Dr. Meng Jing (in chemistry too!), my parents, and my parents-in-law for their love and continuous support. Meng is always there at my hardest times, encouraging me and offering advice. We do not talk about chemistry every day at home, but I did enjoy numerous scientific conversions that started on the sofa in our living room. Plus, I always love the food she created and have been well fed over the last several years. I am excited to continue sharing chemistry with Meng for the rest of

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Abstract Amphiphilic polymers are macromolecules that simultaneously contain hydrophobic and hydrophilic components. These molecules not only attract much attention in academic research but also are important materials in industry. Application areas include detergency, oil field, paints, agriculture, food, cosmetics, and pharmaceutics. This dissertation highlights my efforts since the November of 2007 on three separate systems of amphiphilic polymers, which addresses both the fundamental self-assembly behavior in solution and applications in pharmaceutical formulation.

Chapter 2 describes the self-assembled micelles in water that contain semicrystalline polyethylene (PE) as the core-forming material. Poly(N,N-dimethylacrylamide)– polyethylene (AE) diblock copolymers were chosen as the model system. An AE diblock copolymer with relatively low PE composition resulted in micelles with oblate ellipsoidal cores in water, in which crystalline PE existed as flat disks at the center and rubbery PE resided on both sides. In contrast, a control sample with a rubbery polyolefin as the hydrophobic component resulted in micelles with spherical cores in water. The morphology transition was ascribed to the crystallization of PE. The heat-assisted direct dissolution for sample preparation was identified as a stepwise “micellization– crystallization” procedure. In addition, the morphology of the aggregates exhibited much dependence on the composition of AE copolymers, and wormlike micelles and bilayered vesicles were obtained from samples with relatively high PE compositions. Chapter 3 demonstrates the precise synthesis of glucose-containing diblock terpolymers from a

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polymerizations. The resulting micelles exhibited excellent stability in several biologically-relevant media under in vitro conditions, including 100% fetal bovine serum.

These particles may find applications as serum-stable nanocarriers of hydrophobic drugs for intravenous administration. Chapter 4 presents the development of novel cellulose derivatives as matrices in amorphous solid dispersions for improving the bioavailability of poorly water-soluble drugs in oral administration. Hydroxypropyl methylcellulose (HPMC) was modified with monosubstituted succinic anhydrides using facile anhydride chemistry, and the resulting materials simultaneously contained hydrophobic, hydrophilic, and pH-responsive moieties. Several HPMC esters of substituted succinates exhibited more effective crystallization inhibition of phenytoin under in vitro conditions than a commercial hydroxypropyl methylcellulose acetate succinate (HPMCAS). (341

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1 Background 1

1.1 Amphiphilic Molecules – Small and Large

1.2 Self-assembly of Small Amphiphilic Molecules

1.2.1 Thermodynamics of Micellization

1.2.2 Micellar Polymorphism of Surfactants and Lipids

1.3 Self-assembly of Amphiphilic Diblock Copolymers

1.3.1 Theoretical Modeling

1.3.2 Micellar Polymorphism – Experimental Results

1.3.3 Preparation of Block Copolymer Micelles

1.4 References

2 Self-assembled Polymeric Micelles with Polyethylene Cores in Water 28

2.1 Introduction

2.2 Results and Discussion

2.2.1 Synthesis and Molecular Characterization

2.2.2 Bulk Morphological Properties of AE Diblock Copolymers.............. 37 2.2.3 Oblate Ellipsoidal Micelles with Semicrystalline PE cores................ 42 2.2.4 “Frozen” Micelles

2.2.5 A Stepwise “Micellization–Crystallization” Process

2.2.6 Wormlike Micelles and Bilayered Vesicles with PE Cores................ 58

2.3 Conclusions and Outlook

2.4 Experimental Section

2.5 References

vii 3 Glucose-functionalized, Serum-stable Polymeric Micelles from the Combination of Anionic and RAFT Polymerizations 96

3.1 Introduction

3.2 Results and Discussion

3.2.1 Synthesis and Molecular Characterization

3.2.2 Self-assembly of PG Diblock Terpolymers in Water

3.2.3 Serum-stability of Glucose-functionalized Polymeric Micelles....... 129

3.3 Conclusions

3.4 Experimental Section

3.5 References

4 Hydroxypropyl Methylcellulose Esters of Substituted Succinates as Matrices in Amorphous Solid Dispersions for Enhancing the in vitro Solubility of Phenytoin

4.1 Introduction

4.2 Results

4.2.1 Synthesis and Molecular Characterization

4.2.2 SDDs with Phenytoin and the Effect of Substituent

4.2.3 The Effect of Degree of Substitution

4.2.4 The Effect of Drug Loading.

4.3 Discussion

4.4 Conclusions and Outlook

4.5 Experimental Section

4.6 References

Bibliography 211

A. Spray-dried Dispersions of Hydroxypropyl Methylcellulose (HPMC) Substituted Succinates with Probucol 228 A.1 Results and Discussion

A.2 Experimental Section

A.3 References

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B.1 Results

B.2 Experimental Section

B.3 References


List of Tables

Table 1.1 Thermodynamic properties of five surfactants during the micellization process at or near 25 °C.

Table 2.1 Molecular characteristics of AE and AP diblock copolymers.

Table 2.2 Bulk morphological properties of AE diblock copolymers at 140 °C.

............ 39 Table 2.3 Packing parameters of the micelle aggregates in the “crew-cut” regime......... 69 Table 3.1 RAFT copolymerization of DMA (1, as monomer 1) and TMS-MAG (2, as monomer 2) using PEP-CTA as the macromolecular CTA to afford PEP–poly(DMAgrad-MAG) (PG) diblock terpolymers.

Table 3.2 Molecular characteristics of amphiphilic diblock copolymers and terpolymers.

Table 3.3 Experimental runs towards determining the reactivity ratios of DMA (1, as monomer 1) and TMS-MAG (2, as monomer 2) in free-radical polymerizations in a mixture of toluene and 1,4-dioxane (1:1, v/v) at 70 °C.

Table 3.4 DLS results of the aggregates from the self-assembly of amphiphilic diblock PA and PO copolymers and PG terpolymers in water

Table 3.5 Literature values of refractive index (n) and viscosity (η) of water and four biologically-relevant media at 25 °C.

Table 3.6 DLS results of the aggregates from PA(3-21) and PO(3-25) diblock copolymers and PG(3-24-0.

16) terpolymer in water after 1:5 (v/v) dilutions with five different media.

Table 4.1 Molecular and thermal characteristics of HPMC and HPMC esters.

............. 165 Table 4.2 Dissolution results of crystalline phenytoin and SDDs with nine polymeric matrices at 10 and 25 wt % phenytoin loadings.

Table 4.3 Solubility of polymers in PBS (pH = 6.

5) at 37 °C

Table 4.4 Solubility of phenytoin in PBS (pH = 6.

5) in the absence and presence of several cellulosic polymers at 37 °C.


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List of Figures Figure 1.1 A spherical micelle from the association of dodecyl sulfate in water (adapted from Israelachvili J.

Intermolecular and Surface Forces, Academic Press, London, 1985, p.215).

Figure 1.2 Structures of two-component amphiphilic polymers.

The blue and red circles indicate hydrophilic and hydrophobic repeat units, respectively

Figure 1.3 Micelles of five different morphologies commonly observed in small surfactants and lipids including (A) cylinders, (B) spheres, (C) planar bilayers, (D) flexible bilayers, or vesicles, and (E) inverted micelles.

Reproduced from http://www.vcbio.science.ru.nl.

Figure 1.4 Scheme of a spherical micelle from nonionic block copolymers.

One swollen A corona block is made of a string of correlation blobs, and each correlation blob has a free energy of kBT. Reproduced with permission from Ref10.

Figure 1.5 A phase diagram that illustrates the morphology of micelle aggregates from PEO–PB diblock copolymers in water as a function of NPB and wPEO.

B: bilayered vesicles, C: cylinders, S: spheres, CY: brached cylinders, and N: network. Reproduced with permission from Ref39

Figure 1.6 A phase diagram that illustrates the morphology of micelle aggregates from a PEO227–PS962 diblock copolymer as a function of the concentration of the copolymer and the content of water in the DMF/water mixture.

Reproduced with permission from Ref47.

Figure 2.1 From bottom to the top: 1H NMR spectra of 1,4-PB-OH (3.

1 kg mol–1), PEOH (3.3 kg mol–1), and AE(9–3) (12.6 kg mol–1), respectively

Figure 2.2 From bottom to the top: 1H NMR spectra of 1,4-PI-OH (3.

0 kg mol–1), PEPOH (3.1 kg mol–1), and AP(11–3) (14.0 kg mol–1).

Figure 2.3 SEC traces of 1,4-PI-OH (3.

0 kg mol–1) (solid), PEP-OH (3.1 kg mol–1) (dash), and AP(11–3) (dash dot). The mobile phase was CHCl3 and the temperature was xii 35 °C. The Ɖ values relative to PS standards of 1,4-PI-OH, PEP-OH, and AP(11–3) were 1.06, 1.05, and 1.10, respectively.

Figure 2.4 SAXS profile of molten AE diblock copolymers in bulk at 140 °C.

From bottom to top: (a) AE(0.7–3), (b) AE(0.8–3), (c) AE(1.0–3), (d) AE(1.4–3), (e) AE(2.2– 3), (f) AE(4.0–3), (g) AE(5.9–3), and (h) AE(9.3–3).

Figure 2.5 Temperature dependence of χ as determined through the change of the domain spacing (Dlam) of a lamellae-forming sample, AE(2.

2–3), between 110 and 160 °C....... 41 Figure 2.6 Apparent size distribution of the AE(9–3) and AP(11–3) micelles as generated from the REPES algorithm. The scattering angle was 90°.

Figure 2.7 Representative cryo-TEM images from 0.

5 wt % dispersions of (a) AE(9–3) and (b) AP(11–3), respectively.

Figure 2.8 (a) A representative cryo-TEM image from a 0.

5 wt % dispersion of AE(1.4–

3) in water. (b) SANS profile of AE(1.4–3) micelles in D2O at 25 °C (circles) and 120 °C (squares). The absolute intensity at 120 °C was shifted upward by a factor of 102 for clarity. The solid black curves represent the data modeling assuming an ensemble of noninteracting spheres at 120 °C and oblate ellipsoids at 25 °C, respectively.

Figure 2.9 DSC profile of 3.

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