Combining crystal structure and interaction topology for interpreting functional molecular solids: A study of theophylline cocrystals

Transcription

1 Combining crystal structure and interaction topology for interpreting functional molecular solids: A study of theophylline cocrystals Aditya B. Singaraju1, Kyle Nguyen1, Paula Gawedzki1, Fischer Herald1, Gavin Meyer1, Daniel Wentworth1, Dale C. Swenson2 and Lewis L. Stevens1, *

2 Outline - Functional materials: Does the organization of the molecules in space impact function? - Co-crystallization: A strategy for designing materials from the molecule up - Model pharmaceutical: theophylline - Goal: Co-crystallize theophylline with other molecules to improve its tableting performance - Results: What co-crystal (and crystal structure) best promotes tableting performance? - Conclusions

3 How molecules arrange space (crystal structure) directly impacts a broad variety of pharmaceutical functions. (e.g., solubility, stability and compaction performance) Example: acetaminophen polymorphs (same molecule, just arranged differently) Form I Same molecule Form II Different organization Cannot form tablets Different performance Easily forms tablets

4 Form II of acetaminophen is unstable, i.e. It wants to convert back to the stable Form I, so this approach doesn't work well to improve the tabletability of acetaminophen Can we modify molecular organization, to improve performance, without selecting unstable polymorphs? Co-crystallization is a well-known material design approach. What is a pharmaceutical co-crystal? - The combination of an drug and inert co-former, in a defined stoichiometry, all assembled into the same crystal.

5 - For our project, three co-formers were chosen to co-crystallize with theophylline (THY). Theophylline Acetaminophen Chemical Structures 4-fluoro-3-nitrobenzoic acid p-aminobenzoic acid

6 For THY, the molecules arrange in columns and by introducing a new molecule we expect this organization to change. APAP PABA Each of these coformers will hydrogen bond with THY in different ways. Expect to get different co-crystal structures. THY FNBA Hypothesis: Flat-layered crystal structures improve tableting performance (makes stronger tablets at lower pressures)

7 Methods - Preparation of the Co-crystals Preparation of THY-FNBA Cocrystal: Liquid assisted grinding was used to generate the bulk form of this cocrystal. Preparation of THY-APAP Cocrystal: The THY-APAP cocrystal was prepared using solution mediated phase transformation, a slurry containing equimolar quantities of THY and APAP in acetonitrile was stirred overnight. Preparation of THY-PABA Cocrystal: The THY-PABA cocrystal was synthesized using liquid assisted grinding.

8 Methods Analysis Did we make a co-crystal (a new material)? Differential Scanning Calorimetry Powder X-ray Diffraction How did the material perform? Powder Compaction Test for how dense and strong the tablets are Did the tabletability change? Why? Single-crystal x-ray diffraction Powder Brillouin Light Scattering (p-bls)

9 Co-crystal characterization Two previous materials, THY-APAP and THY-PABA, were previously published. THY-FNBA is a new material, confirmed by DSC and PXRD. Melting points: FNBA: 124 C THY-FNBA: 188 C THY: 273 C

10 Co-crystal characterization Powder pattern:

11 The introduction of a co-former with THY produced 3 new crystalline materials. Flat-layers Columns Different structures have different performance. We expect the layered structures (THY-FNBA, THY-APAP) to be better than the columns (THY, THY-PABA)

12 Making tablets of our co-crystals 1. Load powder into a die and place a punch on top. 2. Apply a given pressure to form a tablet. 3. Store the tablets in a controlled environment. 4. Make tablets at a range of pressures to make a compressibility, compactibility and tabletability plot. Next, we'll determine how strong the tablets are.

13 Initial characterization 1. Measure the mass and dimensions (volume) of the tablet to calculate the density. Porosity is the inverse of density. 2. Use a stress-strain analyzer to determine how much force is take to break a tablet. 3. Calculate the tensile strength (s) using,

14 Compressibility With increasing pressure, the tablet becomes more dense (lower porosity) The more dense = the more compressible The compressibility of THY was increased when crystallized with either FNBA or APAP Better compressibility = better tablets It's easier to compress layers than stacks of columns.

15 Compressibility For the two columnar crystal structures, THY-PABA was less compressible than THY. The inter-digitated columns of THY- PABA resists compression.

16 Compactibility: compactable Compactability Stronger tablet at higher porosity = More THY is intermediate to the compactibility of the two layered co-crystals If a material is both compressible and compactible, then a strong tablet will likely form. At low pressures (higher porosity), THY-FNBA is the most compactible and the most compressible. Expect this material to be the best overall.

17 Tabletability A tabletability plot has tensile strength (how strong the tablets are) vs. Compaction pressure. Increasing tensile strength = stronger tablets, and better performing materials have higher tensile strength In Figure a.), THY-FNBA and THY-APAP material (both layered structures) were generally superior to THY. In Figure b.), the two columnar structures displayed approximately the same performance.

18 Mechanical Properties Mechanical properties characterize how a material responds to stress (pressure). Determined the mechanical properties of all co-crystals using a new technique: powder Brillouin ("brie-on") light scattering Laser light scattering method that measures the sound velocity in materials. For a single-crystal, you measure one sound velocity at a time. For a powder, you get a distribution (shown right) that weuse to calculate mechanical properties. THY-FNBA was found to have the lowest Young's modulus and lowest shear modulus. (Consistent with the tableting studies.)

19 Sound velocities and Intermolecular Interactions Brillouin scattering provides a new way to look how molecules "see" each other in the crystalline state. Sound velocities reflect how strong interactions are in different directions. See acetaminophen polymorphs, re-arranging the molecules = re-arranging the intermolecular forces = change in sound velocities Typically described by hydrogen bonds, but this approach is limited and incomplete. There are no hydrogen bonds between the layers of THY-FNBA and THY-APAP, yet these two structurally similar materials display different performance.

20 Sound velocities & Intermolecular interactions For the two layered structures we see low velocity sound waves, that is, there are directions within these materials with very weak intermolecular interactions. Weaker interactions between the layers = easier to shear = easier to deform = better tablets We can directly measure that strength using Brillouin scattering.

21 Conclusions How molecules arrange in space directly influences the function of the material. Co-crystals are one way to deliberately modify this organization to target an improved material performance. THY-FNBA and THY-APAP co-crystals (both layered structures) made better tablets than THY alone. Two materials may be structurally similar, yet they may not necessarily display the same properties. Differences depend on the intermolecular interactions. Designing new materials you need to look at both crystal structure and interaction topology. This work was Just Accepted for publication in Crystal Growth & Design.

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