Revealing Solid State Polymorphic Phase Transformations as Consequence of Hot Melt Extrusion Processes in Continuous Pharmaceutical Formulations

 

Mr. José R. Hernández Espinell, University of Puerto Rico, Río Piedras Campus,

Faculty of Natural Sciences, Department of Chemistry,

Dr. Torsten Stelzer, University of Puerto Rico, Medical Sciences Campus, School of Pharmacy, Department of Pharmaceutical Science.

 

To replace cost and time intensive conventional batch dominated pharmaceutical solid dosage formulation processes, the pharmaceutical industry is interested in exploring new manufacturing technologies such as hot melt extrusion (HME) that enable continuous formulation of complex products for peroral administration. The determination of the thermodynamic and kinetic behavior as well as the interactions of drug-polymer blends are critical process parameters (CPP), which affect critical quality attributes (CQA) such as crystal size, distribution, morphology, polymorphism, and phase purity. Polymorphism, a phenomenon that enables molecules to exhibit multiple crystalline phases, is one of the most scrutinized CQA during the manufacturing of solid formulations. Polymorphism is estimated to occur in over 80% of molecules that display a pharmaceutical application, affecting primarily their solubility, which correlates with their bioavailability. The inadvertent occurrence of solid-state phase transformation events during a HME process of crystalline pharmaceutical solids dispersed in a molten polymer can lead to undesired polymorphs, which might have an adverse effect on the product’s properties. Therefore, investigating the effects of these CPP is of outmost importance to control CQA of the produced formulation, as well as facilitating the translation of HME into a continuous manufacturing setting with broader applications. The proposed project aims (1) to thoroughly characterize the thermodynamic behavior of drug-polymer blends of different compositions and (2) to understand the solid phase transition kinetics of drug-polymer blends at different temperature and exposure times in simulated HME experiments. It will be done with the ultimate goal of creating a roadmap to control polymorphism of pharmaceutical compounds with various physico-chemical properties dispersed in an equally broad range of polymer matrices during blending, melting, and extruding stages in HME processes. This roadmap will be developed at the applicant’s home institution, the University of Puerto Rico Medical Sciences Campus.

 

Design of Bio-Templated High Porosity Metal Oxide Electrodes

for Dye-Sensitized Solar Cells

Gilberto De Jesús Morales, Dr. Vilmalí López-Mejías, and Dr. Mike Ward

Dye-sensitized solar cells (DSSCs) are a flexible, low cost and easily manufactured alternative to harvest energy from sunlight. Despite these advantages, DSSCs have not presented a significant increase in their efficiency over the past decade. The crystallization of highly porous metal oxide morphologies with well-defined and narrow pore size distribution is a key factor for the successful device operation in DSSCs. The proposed research aims to synthesize highly porous TiO2 with narrow pore distribution using several cellulose-based polymers as soft templates to control the crystallization of the metal oxide, heterogeneously. The effect of the structural diversity of single and multi-component bio-polymer mixtures,  as  well  as  different  deposition  and  processing  methods  will  be  tested systemically to reveal the most efficient bio-template for the DSSC.

 

 

Revealing Polymorphism as Consequence of Hot Melt Extrusion Processes in Continuous Pharmaceutical Formulations

Ms. Desire Ortíz, University of Puerto Rico, Río Piedras Campus, Faculty of Natural Sciences, Department of Chemistry, Dr. Torsten Stelzer, University of Puerto Rico, Medical Sciences Campus, School of Pharmacy, Department of Pharmaceutical Science.

I. Abstract

To replace cost and time intensive conventional batch dominated pharmaceutical solid dosage formulation processes, the pharmaceutical industry is interested in exploring new manufacturing technologies such as hot melt extrusion (HME) that enable continuous formulation of complex products for peroral administration. The determination of the thermodynamic and kinetic behavior as well as the interactions of drug-polymer blends are critical process parameters (CPP), which affect critical quality attributes (CQA) such as crystal size, distribution, morphology, polymorphism, and phase purity. Polymorphism, a phenomenon that enables molecules to exhibit multiple crystalline phases, is one of the most scrutinized CQA during the manufacturing of solid formulations. Polymorphism is estimated to occur in over 80% of molecules that display a pharmaceutical application, affecting primarily their solubility, which correlates with their bioavailability. The careless (re)crystallization of dissolved pharmaceutical compounds subsequent to a HME process can lead to the formation of undesired polymorphic forms, which might have an adverse effect on the product’s properties. Therefore, investigating the effects of these CPP is of outmost importance to control CQA of the produced formulation, as well as facilitating the translation of HME into a continuous manufacturing setting with broader applications. The proposed project aims to harvest favorable drug-polymer interactions to be able to selectively access energetically viable polymorphs in simulated HME experiments. The most promising results will be further studied at the home institution of the applicant, the University of Puerto Rico Medical Sciences Campus. This will be done with the ultimate goal to provide evidence of the enhanced properties of drug formulations developed through control of (re)crystallization events leading to polymorphism during the blending, heating, and extruding steps related to HME processes.

 

Creating a New Type of Swimmer: The Thermal Marangoni Effect

 Bilyana Tzolova, Postdoc: Michelle Driscoll, PI: Paul Chaikin                                                                                                                                                                              

 

Active matter systems are driven systems, meaning they are not in equilibrium. As a result, they can consume energy to create systematic movement. We want to create a new kind of active matter system which is driven by heat consumption. To make such a new swimmer we will create a droplet with a darker spot on one side. When light is shone on the droplet the darker area will absorb heat at a faster rate than the rest of the droplet. This will create a temperature gradient across the droplet which will result in a difference in surface tension inside the droplet. The liquid inside will start flowing from areas of high surface tension to low surface tension as a result of the Marangoni effect. The flow on the inside of our droplet will give rise to a flow on the outside of the droplet which will power our swimmer to move. The benefit of creating a swimmer driven by heat is that its energy source will never run out so our swimmer can be in constant movement. We are exploring three different emulsion systems as candidate heat-powered swimmers: double emulsion, gold-patch emulsions, and electrostatically stabilized emulsions.

 

 

 

A DNA Crystal Designed to Contain 4 Molecules Per Asymmetric Unit

Joshua Nott, Yoel P. Ohayon and Nadrian C. Seeman

 

Tensegrity triangle DNA motifs self-assemble into a 3-D lattice through sticky end cohesion.1 While only a single motif was used to produce the first crystal lattice, in more recent experiments two different tensegrity triangle motifs have been shown to self-assemble into a single lattice with two molecules in the crystallographic unit.2 The motifs differed in the sequences of the strands that composed the triangle motif as well as in the sticky end bases that enable cohesion between the motifs. However, sticky end cohesion was achieved between the separate motifs by designing sticky ends so that each molecule was complementary to the other and not to itself.2 We are extending this method by using four different triangle motifs to form a lattice. We predict that the motifs will arrange themselves in a 4-way alternating pattern via complementary sticky end cohesion, thereby self-assembling into a crystalline lattice.

 

 

1J. Zheng, J.J. Birktoft, Y. Chen, T. Wang, R. Sha, P.E. Constantinou, S.L. Ginell, C. Mao, & N.C. Seeman, From Molecular to Macroscopic via the Rational Design of a Self-Assembled 3D DNA Crystal, Nature 461, 74-77 (2009).

2T. Wang, R. Sha, J. Birktoft, J. Zheng, C. Mao, & N.C. Seeman, A DNA Crystal Designed to Contain Two Molecules per Asymmetric Unit, J. Am. Chem. Soc. 132 (44), 15471-15473 (2010).

 

 

 

Biocompatible-Tailored-Nanocrystals-Drug Nanocarriers

For Colorectal Cancer Treatment

 

Kevin Rivera, Dr. Vilmalí López-Mejías, and Dr. Mike Ward

 

The project consists of the gelation of natural polysaccharides, alginate and chitosan, at the nanoscale, to encapsulate nanocrystals of active pharmaceutical ingredients (APIs) for drug delivery applications, specifically, colorectal cancer treatment. The project addresses the poor bioavailability following the oral administration of cancer-related therapeutic agents. The APIs of interest are 5-fluorouracil and doxorubicin both which have been used to treat colorectal cancer. Chitosan and alginate were selected as the carrier matrix for the APIs because they both are non-toxic, and have previously shown positive feedback in existing colorectal cancer treatments. These research efforts will improve the solubility, stability, and bioavailability of these APIs by reducing and controlling the crystal size, and providing selective access to viable polymorphs of the APIs within the confined polymer matrix. Additionally, chitosan will be grafted covalently with folic acid to improve the specificity of the nanoparticles to cancerous cells lines during a possible treatment with this proposed drug delivery system.

 

Temperature-Accelerated Molecular Dynamic Simulations of Polymorphism of Acenes

 Eric Lansing MRSEC REU Program New York University lansing@kth.se

 

The summer project assigned to me was primarily to study the polymorphism of acenes. Acenes such as anthracene, pentacene,.... are important for their use as organic semiconductors. In addition, organic molecules, such as acenes, often form numerous and varied crystalline structures with different properties, and predicting what these are and how they form often proves to be challenging. The rate of crystalizing is most signicantly governed by thermodynamics and the free energy found within the system. Computational studies often target specific order parameters and/or the shape of the unit cell in order to distinguish the crystalline arrangements of molecules. In our studies, these will be subject to enhanced sampling techniques in order to accelerate the discovery of polymorphs and provide a ranking of these based on free energy. Foremost, I will be studying various aspects of the polymorphism of anthracene and also aid in the research regarding the polymorphism of naphthalene. This will mostly be studied with the aid of enhanced molecular dynamics calculations. Furthermore, I have been asked to help out with blind structure prediction tests, for which candidates are due at the end of the summer.

 

 

Programmable bio-nano-chip system: a flexible diagnostic platform that learns

                           Research synopsis, Maria Qvarnström – MRSEC Summer REU Program

Department of Biomaterials, New York University College of Dentistry, New York, NY,

USA

 

For some years now, the use of bimomarkers has become increasingly intrinsic to the practice of medicine and clinical decision-making. Clinically validated biomarkers provide healthcare providers and clinicians a means to quickly and objectively measure, track, and diagnose a patient’s past and present physiological state for a wide range of conditions. As a result, biomarkers help patients receive appropriate care, which in turn helps reduce healthcare costs. Biomarker-based tests are typically developed by diagnostic companies, and are often purchased and performed by medical testing companies. Biomarkers also aid pharmaceutical companies in quickly and efficiently screening their candidate drug products for dosing, pharmacokinetics, safety, and efficacy, thus simultaneously speeding up development and lowering the costs of drug. Upstream in the R&D continuum, early-stage researchers look for biomarkers to help better understand disease etiologies. Because of the significant promise of biomarkers to improve healthcare, research in the field has risen rapidly in recent years.

To aid in providing more efficient healthcare and diagnostic systems the McDevitt lab has recently developed the programmable bio-nano-chip (p-BNC) system. This platform technology combines unique chem- and biosensing capabilities with powerful machine learning algorithms to provide novel and intuitive single-valued indices across several major diseases. The internship will focuses mainly on development and refinement of these chip-based sensors and the research targets the development of molecular level insights into biomarker expression as they relate to early disease detection.

 

 

Hydrophobic Coatings of Silica Colloids

 NYU MRSEC: Research Synopsis

Daniel Estabrook

 

                      In recent years, bottom-up approaches to material syntheses have lead to an expansive collection of building blocks that, under such methods, self-assemble through either a physical principle (ex. hydrogen bonding, depletion interactions, etc.) or an applied driving force (ex. initiation of intersystem crosslinking). Future materials with applications including drug delivery, sensors, catalysis, and molecular electronics will be built on principles of self-assembly often found in biological molecules—namely, reliability and structural precision. However, a common complication in assembling colloidal particles into more complex target structures is the lack of specific directional bonding between such colloids.

In response to this problem, the Weck research group has offered a solution within a new class of anisotropic “patchy” colloids—that is, colloids functionalized with interaction “patches” at discrete surface locations that induce self-assembly through highly directional interactions. The appropriate design of these patches is of critical importance, as the resulting colloidal network structure will mirror, for instance, the symmetry and reversibility of the patches. Such patches may be composed of associating organic ligands, synthetic polymers or complementary molecules like DNA. Over the next ten weeks, I will be spending time within the Weck research group studying a new generation of patchy particles under a graduate mentor, Xiaolong Zheng. It is my hope that this work will add a greater understanding to the ways in which this class of colloids may serve as a building block for the assembly of more complicated network structures with common world use.

 

Nanoparticle Encapsulation in Micellar Capsules

                                              Darlan Barbosa da Silva PI: Marc Walters

 

Dr. Walters’ group is interested in research and characterization of reverse micelles using the cationic surfactant Cetyl Dimethyl Ammonium (CDA) to synthesize nanoparticles of D­glucuronic acid. Such Nanoparticles are produced via crosslinking using the crosslinking agent epichlorohydrin. These capsules have been proved to have an important role in the drug delivery of pharmaceutics and delayed­released formulations. Specifically, our interest is to encapsulate Prussian Blue (Fe4 [Fe(CN)6 ]3 ) inside these nanoparticles, which could be applied in the diognose area and radiographic image.

 

 

Study of the Quenching Mechanisms of Tetrazine Cycloadditions 

Maria De Abreu Pineda

Research Group: Daniela Buccella

Inverse electron demand Diels-Alder reactions between tetrazines and strained alkenes have broad applications from bioconjugation of fluorophores to the functionalization of surfaces. These reactions are attractive due to their fast kinetics, the generation of only one by-product (N2), as well as their fluorogenic properties, creating an emissive product. Previous studies suggest that fluorophore quenching by tetrazines occurs due to an energy transfer mechanism, which is absent in the product of cycloadditions. However, on occasion, the final product is not as emissive as expected. The main goal of this research is to investigate possible fluorescence quenching mechanisms of the products of tetrazine cycloadditions. Understanding such mechanisms may lead to better fluorogenic reactions with maximized emission of the conjugated fluorophores.

 

 

 

Characterization of a Protein Block Copolymer for Drug Delivery Applications

 

Kyle Okino

Research Group: Dr. Montclare

 

The Montclare lab has engineered a protein block copolymer comprised of a pentameric alpha-helical coiled-coil domain derived from the cartilage oligomeric matrix protein (C) and varying numbers (1-5) of elastin-like peptide repeat domains (E)1-2. The C domain is capable of binding small hydrophobic molecules and the E domain undergoes a temperature sensitive transition from a disordered state to a beta-sheet structure1-3.

These protein block copolymers were designed for the purpose of novel drug delivery vehicle development. The intention is to encapsulate hydrophobic drug molecules in the C domain and increase the temperature to alter the structure of the E domain thereby stimulating drug release. From experimentation, it was found that altering the size of the E domain affects the small molecule drug binding and thermoresponsive properties of the block polymers2. As shown by the Montclare lab, thermoresponsiveness can further be altered with the use of fluorinated amino acids4.

Fluorine is an isosteric substitute for hydrogen with a van der Waals radius slightly greater than hydrogen. Strategic replacement of hydrogen with fluorine in amino acids can result in minimal structural and functional changes5. Fluorine, however, can impart hydrophobic properties upon amino acids and significantly impact the thermostability of proteins4-5. Fluorine, being essentially absent in all biological molecules, can also be used a probe for 19F NMR and MRI5.

                Over the summer, I will be carrying out experiments on a protein block copolymer, dubbed CE2-RGD, where leucine will be replaced with 5,5,5-trifluoro-L-leucine. This will be achieved by recombinant protein expression in an auxotrophic E. coli. I will become familiar with protein expression and purification techniques for further characterization of the size, secondary structure, and drug binding properties of this protein.

 

 References

1.     Haghpanah, J.S.; Yuvienco, C.; Civay, D.E., Barra, H.; Baker, P.J.; Khapli, S.; Voloshchuk, N.; Gunasekar, S.K; Muthukumar, M.; Montclare, J.K. Artificial protein Block Copolymers Comprising Two Distinct Self-Assembling Domains. ChemBioChem Communications. 2009 10:2733-2735

2.     Dai, M.; Haghpanah, J.S.; Singh, N.; Roth, E.W.; Liang, A.; Tu, R.S.; Montclare, J.K. Artificial Protein Block Polymer Libraries Bearing Two SADs: Effects of Elastin Domain Repeats. Biomacromolecules. 2011 12:4240-4246

3.     Gunasekar, S.K.; Asnani, M.; Limbad, C.; Haghpanah, J.S.; Hom, W.; Barra, H.; Nanda, S.; Lu, M.; Montclare, J.K. N-Terminal Aliphatic Residues Dictate the Structure, Stability, Assembly, and Small Molecule Binding of the Coiled-Coil Region of Cartilage Oligomeric Matrix Protein. Biochemistry. 2009 48:8559-8567

4.     Yuvienco, C.; More, H.T.; Haghpanah, J.S.; Tu, R.S.; Montclare, J.K. Modulating Supramolecular Assemblies and Mechanical Properties of Engineered Protein Materials by Fluorinated Amino Acids. Biomacromolecules. 2012 13:2273-2278

5.     Buer, B.C.; Marsh, E.N.G. Fluorine: A new element in protein design. Protein Science. 2012 21;4:453-462