CHMS 5201 & 5202: Anal Instrumentation Lab I & II

Experiment 9: Crystal Structure  Determination of Pharmaceutical Cocrystals and Metal Organic Frameworks (MOFs) by Single XRD

Reference

1.Dejan-Kresimir Bucar, Rodger F. Henry, Xiaochun Lou, Richard W. Duerst, Leonard R. MacGillivray, and Geoff G. Z. Zhang, Crystal Growth & Design, 2009, Vol. 9,No. 4, 1932-1943

2.Hideki Hayashi, Adrien P. Côté, Hiroyasu Furukawa, Nature Materials, 2007, 6 (7), 501-506

Objectives

•    To practice solvothermal synthesis of pharmaceutical co-crystals and metal organic frameworks

•    To familiarize with single-crystal XRD instruments

•    To analyze single-crystal XRD data with crystallographic software

Introduction

X-Ray crystallographic analysis is a powerful method to provide direct information on molecular structures at atomic level. This core technique provides structural details such as molecular arrangements and bond lengths. It can be used not only as a characterization tools for synthetic chemist determining the precise chemical arrangements, but also play an important role in understanding the physical nature and the materials by studying its various weak intermolecular interactions between molecules.

Crystal Engineering has grown and developed over the past 50 years, which is related to the understanding of intermolecular interactions in crystal packing and use this knowledge to design new crystalline solids with desired physical and chemical properties. It can be classified into two main areas: Study of (1) Coordination Networks and (2) Molecular Materials.

Coordination Networks, commonly known as metal organic frameworks (MOF) or porous coordination network (PCN), consist of ultrahigh porosity and enormous internal surface areas ranges from  1-D to 3-D coordination polymers. By combining two components, metal ion or cluster and organic linker, the structure of the porous materials can be readily engineered in composition, structure and functionality. Their interesting properties include wide range of important applications include gas storages, separation and sensing.

Molecular Materials involves the studying of polymorphs and co-crystals. Polymorphs refer to the same type of materials that can form two or more crystal packing while co-crystals refer to two or more types of molecular or ionic compound crystallize in a single crystalline phase in a particular stoichiometric ratio. They both play an important role in pharmaceutical formulation as their solubility, bioavailability, solid-state stability is greatly depending on their structures.

In this experiment, the study of pharmaceutical co-crystals and metal Organic Frameworks were demonstrated by two  systems  via  solvothermal  synthesis:  (1)  Synthesis  of  Caffeine:4-hydroxybeznoic  acid  co-crystal  and  (2) Synthesis of zeolitic imidazolate frameworks (ZIF).

Caffeine, a worldwide mostly used pharmaceutical model compound, was heavily studied as a psychoactive drug. Researches shows its pharmaceutical performance can be greatly improved via co-crystal phase formation with aromatic carboxylic acids (1) . The interaction always involves one of more heterosynthon hydrogen bond between acid and caffeine imidazole moiety. In this experiment, the system Caffeine:4-hydroxybeznoic acid is chosen as it can form both 1:2 and 2:1 co-crystal with change of condition. Different supermolecular heterosynthons can be examined in the structural isomers and reveal the impact of structural variation.

Zeolitic imidazolate frameworks (ZIF) are known as analogues of SiO2. Various porous materials can be readily engineered for composition, structure and functionality with different reaction conditions. In this experiment, two 3-D networks, SOD topology (ZIF-8) and quartz topology, will be synthesized (2) . SOD topology (ZIF-8) consist of large cavities which is useful for solvent/gas absorption application, while the quartz analogue is sensitive to thermal changes and consist of non-linear piezoelectricity.

Experimental Procedure

A. Preparation of Crystalline Samples

Since most part-time students are unable to prepare these, several different materials will be prepared for later analysis that all groups will use.

General Solvothermal Synthesis

1.   Place all the mixture into Teflon cup (Day 1)

2.   Introduce corresponding solvents into the Teflon cup (Day 1)

3.   Place Teflon cup in stainless steel container and seal container (Day 1)

4.   Place container + Teflon cup into oven at 80/110oC for various durations (Day 1)

5.   Allow to cool slowly to room temperature (Day 2)

6.   Unscrew stainless steel container (Day 2)

7.   Filter the mixture in the Teflon cup using suction filtration (Day 2)

8.   Wash with water then ethanol (Day 2)

9.   Continue filtering with suction filtration for 5-10 minutes (Day 2)

10. Weigh the crystals and calculate the yield (Day 2)

1.   Pharmaceutical co-crystals Caffeine:4-hydroxybenzoic acid (Day 1)

Synthesis of Caffeine:4-hydroxybenzoic acid 2:1 co-crystal (Cpd 1)

Caffeine (1 mmol, Fw 194.19, 194 mg), 4-hydroxybeznoic acid (0.5 mmol, Fw 138, 75 mg) and 2 mL Acetonitrile were placed into an air-tight vial. The mixture was heated at 80oC for 2 hours. On cooling colorless block obtained by filtration.

Synthesis of Caffeine:4-hydroxybenzoic acid 1:2 co-crystal (Cpd 2)

Caffeine (0.5 mmol, Fw 194.19, 97 mg), 4-hydroxybeznoic acid (1 mmol, Fw 138, 138 mg) and 2 mL Acetonitrile were placed into an air-tight vial. The mixture was heated at 80 oC for 2 hours. On cooling colorless block obtained by filtration.

2. ZeoliticImidazolate Frameworks: SiO2 analogues (Day 1)

Synthesis of Zeolitic imidazolate frameworks with SOD topology (Cpd 3)

A mixture of Zinc acetate (0.183 g, 1 mmol), 2-methylimidazole (0.328 g, 4 mmol), potassium hydroxide (0.112 g, 2 mmol) and ethanol (2 mL) was placed into a Teflon-lined autoclave. Then, the autoclave was sealed and heated at 110 ℃ for 1 day. After being cooled to room temperature, colorless crystals were filtered by filtration.

Synthesis of Zeolitic imidazolate frameworks with Quartz topology (Cpd 4)

A mixture of Cadmium acetate (0.230 g, 1 mmol), 2-ethylimidazole (0.384 g, 4 mmol), potassium hydroxide (0.112 g, 2 mmol) and H2O (2 mL) was placed into a Teflon-lined autoclave. Then, the autoclave was sealed and heated at 110 ℃ for 1 day. After being cooled to room temperature, colorless crystals were filtered by filtration.

Single Crystal X-ray Diffraction (Day 2)

Crystals will be mounted for quick checking of the suitability of the crystal for analysis and unit cell determination maybe carried out.

The choice of ideal crystal – size, habit and singularity will be discussed. Crystals maybe glued to a glass fiber for mounting on the diffractometer, or immersed in paratone liquid before freezing. Each group member will be responsible for one sample.

The optical centering of the crystal will be demonstrated and the procedure for cell check carried out.  Ideally for each session one crystal will be selected for a full data collection and crystal structure determination.

A Crystallographic software OLEX2 (free download http://www.olexsys.org/) will be introduced step by step. We will go through how to process the x-ray data from two examples (Cpd1 and Cpd3) in details.

Results

1)   Use OLEX2 software to solve the data for Cpd 2, output a figure represent the crystal structure and attached them in your report. Please also submit your .res file.

2)   Please comment on the relatively high R value and the large Q-peak presence in Cpd 1

3)   Please suggest what will happen if we try out the reaction in a ratio of 1:1 caffeine:4-hydroxybenzoic acid instead.

4)   Please use OLEX2 to output a figure represent the packing of Cpd 3 and 4. Briefly comment on their differences

5)   Cpd 3 & 4 are well-known materials. Please list out one important application for each Cpd and explain how they work.